CN102065853A - Process for preparing and drying solid rasagiline base - Google Patents
Process for preparing and drying solid rasagiline base Download PDFInfo
- Publication number
- CN102065853A CN102065853A CN2009801235603A CN200980123560A CN102065853A CN 102065853 A CN102065853 A CN 102065853A CN 2009801235603 A CN2009801235603 A CN 2009801235603A CN 200980123560 A CN200980123560 A CN 200980123560A CN 102065853 A CN102065853 A CN 102065853A
- Authority
- CN
- China
- Prior art keywords
- aminoidan
- propargyl
- water
- rasagiline
- crystallization
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 239000007787 solid Substances 0.000 title claims abstract description 155
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
- C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
- C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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Abstract
Disclosed is crystalline R( + ) -N-propargyl-1-aminoindan containing water at an amount of less than 0.5% by weight and a pharmaceutical composition comprising the same, and the process for the manufacture and the validation thereof. Also disclosed is a process for the preparation of solid rasagiline base.
Description
The application requires the interests of the United States Patent (USP) provisional application submitted on June 19th, 2008 number 61/132,487, and the full content of this provisional application is by with reference to being incorporated into this.
In this application with reference to various publications and publication.The comprehensive disclosed content of these publications be used as with reference to and in the application so that more completely describe with the present invention under prior art.
Background technology
R (+)-N-propargyl-1-aminoidan (R (+)-N-propargyl-1-aminoindan, " R-PAI "), be also referred to as rasagiline (rasagiline), be reported as the selective depressant of a kind of monoamine oxidase B (" MAO-B "), be used for the treatment of Parkinson's disease (Parkinson ' s disease) and multiple other situations.
The rasagiline mesylate is got permission as monotherapy or as the auxiliary Parkinson's disease that is used for the treatment of of other therapies.Referring to, AGILECT for example
, Physician ' s Desk Reference (2007), 61th Edition, Thomson Healthcare.
United States Patent (USP) 5,532,415 have disclosed the synthetic of rasagiline, embodiment 3 has wherein described after chromatographic isolation, as a kind of recovery of oil rasagiline alkali.United States Patent (USP) 5,532, other the synthetic examples in 415 shown from its crude product form or its racemic modification and prepared rasagiline salt, and this racemic modification further forms pharmaceutically acceptable salt with suitable acid reaction.
In Pharmaceutical composition, degree of crystallinity is that of active pharmaceutical ingredient conforms with ideal character.Crystalline solid is convenient to process and be mixed with most pharmaceutical dosage forms.Rasagiline alkali can go out with isolated in crystalline form.
Utilizing the solid rasagiline alkali of crystallization preparation is not complete usually " do ", solvent still contained really.Need a kind of suitable method and remove solvent, drying solid rasagiline alkali makes again simultaneously because the yield losses that distillation causes is reduced to minimum.
Brief summary of the invention
The invention provides crystallization R (+)-N-propargyl-1-aminoidan that water content is lower than 0.5% weight.
The present invention also provides a kind of pharmaceutical composition, and it comprises water content at the R of 0.5% weight (+)-N-propargyl-1-aminoidan and medicinal acceptable carrier.
The present invention also provides the method for a kind of drying solid R (+)-N-propargyl-1-aminoidan, and this method comprises that the suitably long down time of the pressure that makes solid R (+)-N-propargyl-1-aminoidan be in temperature below 40 ℃ and 2-1013.3 mbar is with dry this solid R (+)-N-propargyl-1-aminoidan.
The present invention also provides a kind of preparation to comprise crystallization R (+)-N-propargyl-1-aminoidan and the medicinal method of accepting the pharmaceutical composition of carrier of water content in 0.5% weight, and this method comprises: a) under the pressure of temperature below 40 ℃ and 2-1013.3mbar to the dry suitably long time of solid R (+)-N-propargyl-1-aminoidan with dry this solid R (+)-N-propargyl-1-aminoidan; And b) will lump together by exsiccant R (+)-N-propargyl-1-aminoidan and the medicinal acceptable carrier that step a) obtains, thereby prepare this pharmaceutical composition.
The present invention also provides the method for medicine checking that a kind of production comprises crystallization R (+)-N-propargyl-1-aminoidan and at least a medicinal acceptable carrier that is used to distribute batch, and this method comprises: a) produce a collection of this medicine; B) measure the moisture weight content of the sample of this batch; And c) only when the water content of crystallization R (+)-N-propargyl-1-aminoidan of this batch is lower than 0.5% weight, verifies this batch.
The present invention also provides the method for a kind of production crystallization R (+)-N-propargyl-1-aminoidan, and this method comprises:
A) salt of purification R (+)-N-propargyl-1-aminoidan;
B) with R (+)-N-propargyl-1-aminoidan salt formation solution soluble in water of this purification;
C) described solution is cooled to 0-15 ℃;
D) described solution being alkalized to pH is that 9.5-12.5 forms a suspension; And
E) described crystallization rasagiline R (+)-N-propargyl-1-aminoidan is separated from this suspension.
The present invention also provides the method for a kind of production crystallization R (+)-N-propargyl-1-aminoidan, and this method comprises:
A) obtain R (+)-solution of N-propargyl-1-aminoidan in a kind of water-soluble organic solvent;
B) and together with this solution and water;
C) described solution is cooled between 0-20 ℃, forms crystallization R (+)-N-propargyl-1-aminoidan;
D) crystallization R (+)-N-propargyl-1-aminoidan is separated; And
E) if the amount of S (+)-N-propargyl-1-aminoidan greater than 0.1% weight of the R (+) that in step d), is obtained-N-propargyl-1-aminoidan total amount, then repeating step is a)-d).
Brief description of drawings
Fig. 1 has shown that at 60 ℃ pressure is to the influence of liquid rasagiline alkali evaporation/rate of sublimation.
Fig. 2 has shown the influence of pressure and temperature to solid rasagiline alkali rate of sublimation.
Temperature variation curve when Fig. 3 has compared on a small scale with mass preparation rasagiline alkali.
Fig. 4 has shown granularity and the shape of rasagiline tartrate before purification.
Fig. 5 has shown granularity and the shape of rasagiline tartrate behind purification.
The detailed description of invention
Because fusing point is low and can distil, and has observed and has utilized routine techniques to come drying solid Lei Shajilan can cause yield losses.
Provide a kind of allowing because the yield losses that causes of distillation is reduced to the method for desolvation drying solid rasagiline base under the condition of minimum degree at this.
The invention provides the crystallization R (+) that water content is lower than 0.5% weight-N-propargyl-1-aminoidan.
In an embodiment, the moisture content of the amino indenes of this crystallization R (+)-N-propargyl-1-is not higher than 0.06% weight.
The present invention also provides a kind of pharmaceutical composition, and it comprises water content at the R of 0.5% weight (+)-N-propargyl-1-aminoidan and medicinal acceptable carrier.
In an embodiment, this pharmaceutical composition is formulated for oral. In another embodiment, said composition is formulated for through skin and uses. In also having an embodiment, this medicinal composition is the form of transdermal patch.
The present invention also provides the method for a kind of drying solid R (+)-N-propargyl-1-aminoidan, and the method comprises under the pressure that makes solid R (+)-N-propargyl-1-aminoidan be in temperature below 40 ℃ and 2-1013.3mbar that the suitably long time is with dry this solid R (+)-N-propargyl-1-aminoidan.
In an embodiment, hothouse is heated to below 40 ℃. In another embodiment, hothouse is heated to below 35 ℃. In also having an embodiment, hothouse is heated to below 25 ℃. In also having an embodiment, hothouse is heated to below 22 ℃.
In an embodiment, the pressure of hothouse is between the 2-1013.3mbar. In another embodiment, the pressure of hothouse is between the 3-500mbar. In also having an embodiment, the pressure of hothouse is between the 5-250mbar. In also having an embodiment, the pressure of hothouse is between the 10-100mbar. In also having an embodiment, the pressure of hothouse is between the 20-50mbar. In also having an embodiment, the pressure of hothouse is between the 22-28mbar. In also having an embodiment, the pressure of hothouse is between the 20-25mbar. In also having an embodiment, the pressure of hothouse is between the 2-3mbar. In also having an embodiment, the pressure of hothouse is between the 4-5mbar. In also having an embodiment, the pressure of hothouse is between the 2-5mbar.
In an embodiment, hothouse is heated to below 40 ℃, and the pressure of this hothouse is between the 2-1013.3mbar. In another embodiment, hothouse is heated to below 35 ℃, and the pressure of this hothouse is between the 20-50mbar. In also having an embodiment, hothouse is heated to below 35 ℃, and the pressure of this hothouse is between the 22-28mbar. In also having an embodiment, hothouse is heated to below 35 ℃, and the pressure of this hothouse is between the 20-25mbar. In also having an embodiment, hothouse is heated to below 25 ℃, and the pressure of this hothouse is between the 22-28mbar. In also having an embodiment, hothouse is heated to below 25 ℃, and the pressure of this hothouse is between the 20-25mbar.
In another embodiment, be at least 45 hours drying time.
So-called temperature below 40 ℃ refers to that in this temperature scope all divide position and integer-bit degree centigrade all to be disclosed as clearly partial content of the present invention. Therefore, 39.9,39.8,39.7 ℃ ... and 39,38,37 ℃ ..., wait to be disclosed as embodiments of the invention. Equally, so-called pressure between 2-1013.3mbar refers to that all branch positions and the integer-bit in this pressure scope all is disclosed as partial content of the present invention clearly. Therefore, 2.1,2.2,2.3 ... 1013.1 1013.2,1013.3 are included in wherein as embodiments of the invention.
The present invention also provides comprise water content in the method for the pharmaceutical composition of the crystallization R (+) of 0.5% weight-N-propargyl-1-aminoidan and medicinal acceptable carrier a kind of the preparation, and the method comprises: a) under the pressure of the temperature below 40 ℃ and 2-1013.3mbar to dry suitably long time of solid R (+)-N-propargyl-1-aminoidan with dry this solid R (+)-N-propargyl-1-aminoidan; The R (+) of the drying that and b) will a) be obtained by step-N-propargyl-1-aminoidan and medicinal acceptable carrier are combined, thus pharmaceutical compositions.
Other embodiment of the present invention have description in specification.
The present invention also provides the method for medicine checking that a kind of production comprises crystallization R (+)-N-propargyl-1-aminoidan and at least a medicinal acceptable carrier for distributing batch, and the method comprises: a) produce one batch of this medicine; B) measure the moisture weight content of the sample of this batch; And c) only when the water content of the crystallization R (+) of this batch-N-propargyl-1-aminoidan is lower than 0.5% weight, verifies the distribution of this batch.
In an embodiment, only when the water content of the crystallization R (+) of this batch-N-propargyl-1-aminoidan was lower than 0.06% weight, this batch was verified.
The present invention also provides the method for a kind of production crystallization R (+)-N-propargyl-1-aminoidan, and the method comprises:
F) salt of purification R (+)-N-propargyl-1-aminoidan;
G) with the salt formation solution soluble in water of R (+)-N-propargyl-1-aminoidan of this purification;
H) described solution is cooled to 0-15 ℃;
I) described solution being alkalized to pH is that 9.5-12.5 forms a suspension; And
J) described crystallization rasagiline R (+)-N-propargyl-1-aminoidan is separated from this suspension.
In an embodiment of this method, step a) comprises:
I) with the salt formation solution soluble in water of this R (+)-N-propargyl-1-aminoidan;
Ii) in this solution, add a kind of water-soluble organic solvent;
Iii) this solution is cooled to about 0-10 ℃ temperature; And
Iv) from this suspension, obtain the salt of R (+)-N-propargyl-1-aminoidan of purification.
In another embodiment of this method, with respect to R (+)-N-propargyl-1-aminoidan before the crystallization, the optical purity of the salt of R (+)-N-propargyl-1-aminoidan of this purification that is v) obtained from step I increases.
In another embodiment of the present invention, the salt of this R (+)-N-propargyl-1-aminoidan is tartrate.
The present invention also provides the method for a kind of production crystallization R (+)-N-propargyl-1-aminoidan, and this method comprises:
A) obtain R (+)-solution of N-propargyl-1-aminoidan in a kind of water-soluble organic solvent;
B) and together with this solution and water;
C) this solution is cooled between 0-20 ℃, forms crystallization R (+)-N-propargyl-1-aminoidan;
D) crystallization R (+)-N-propargyl-1-aminoidan is separated; And
E) if the amount of S (+)-N-propargyl-1-aminoidan greater than 0.1% weight of the R (+) that in step d), is obtained-N-propargyl-1-aminoidan total amount, then repeating step is a)-d).
In one embodiment of the invention, this water-soluble organic solvent is a kind of alcohol.
In another embodiment of this method, this alcohol or ethanol, or isopropyl alcohol, or the mixture of ethanol and isopropyl alcohol.
In another embodiment of this method, with respect to R (+)-N-propargyl-1-aminoidan before the crystallization, the optical purity of this crystallization R (+)-N-propargyl-1-aminoidan increases.
Here employed " PAI " refer to N-propargyl-1-aminoidan (N-propargyl-1-aminoindan).
Here employed " medicine " (drug substance) refers to the active component in the medicine, it is diagnosis, treatment, mitigation, processing or the prevention of disease or influences human body or any functional structure of animal body, pharmacological activity or other direct effect are provided.
Here employed " medicine " (drug product) refers to and makes forms of pharmaceutical compositions, and it includes medicine and at least a medicinal acceptable carrier.
Here employed " medicinal acceptable carrier " (pharmaceutically acceptable carrier) refers to a kind of carrier or excipient, it is applicable to human body and/or animal and does not have and the adverse side effect of the discomfort that reasonably interests/risk-ratio is suitable (toxicity for example, stimulation, and anaphylaxis).
Here employed " stability test " (stability testing) refer to the experiment of under particular time interval and multiple environmental condition (for example temperature and humidity), carrying out test a kind of medicine in experience its specify shelf life in the phase whether and to which kind of degree degraded.Specific test condition and time are meant that those can quicken the condition of medicine in its shelf life situation that expection can run in the phase.
R (+)-N-propargyl-1-aminoidan can be acquired with crystal form, and when characterizing by the powder x-ray diffraction collection of illustrative plates, 2 θ have located peak value for 16.1 and 16.9 ° ± 0.2 ° 8.5,12.6.It can also further be characterized by powder x-ray diffraction collection of illustrative plates 2 θ 20.3,20.9, has located peak value for 25.4,26.4 ° and 28.3 ± 0.2 °; Perhaps fusing point is 38-41 ℃.
A kind of method for preparing crystallization R (+)-N-propargyl-1-aminoidan, it comprises: a) with the formation solution soluble in water of R (+)-N-propargyl-1-aminoidan; B) described solution is cooled to about 0-15 ℃; C) the extremely about pH 11 of described solution alkalization is formed suspensions; And d) from this suspension, obtains described crystallization rasagiline R (+)-N-propargyl-1-aminoidan.
The another kind of method for preparing crystallization R (+)-N-propargyl-1-aminoidan comprises: first organic solution that a) obtains liquid R (+)-N-propargyl-1-aminoidan; B) under the vacuum this solvent evaporated from this first organic solution fully and form a residue; C) this residue is dissolved in formation second organic solution in second organic solvent; D) under the vacuum this second solvent evaporated from this second organic solution fully and form second residue; And e) this second residue is remained on forms crystallization R (+)-N-propargyl-1-aminoidan under 0-25 ℃ the temperature.
Also have a kind of method for preparing crystallization R (+)-N-propargyl-1-aminoidan to comprise: a) to obtain R (+)-solution of N-propargyl-1-aminoidan in a kind of water-soluble organic solvent; B) and together with this solution and hydration; C) should be cooled to formation crystallization R (+)-N-propargyl-1-aminoidan between 0-20 ℃ by described solution; And d) crystallization R (+)-N-propargyl-1-aminoidan is isolated.
The dissolubility of crystallization rasagiline alkali in water is lower than many rasagiline salt, its mesylate especially, and it is water miscible.The dissolubility of rasagiline mesylate in water is 92mg/ml when pH 6.7, is 570mg/ml when pH 3.3, and the two is all measured down at 25 ℃.Under same temperature, the dissolubility of rasagiline alkali in water is 5.5mg/ml when pH 11.
Crystallization rasagiline alkali can be used as a kind of synthetic intermediate with preparation rasagiline salt, for example rasagiline mesylate or rasagiline tartrate.Crystallization rasagiline alkali dissolves in the solvent, forms medicinal acceptable acid-addition salts with acid reaction.The crystallization of rasagiline alkali might provide the purification that replenishes of its acid-addition salts.
Water solublity is a key property of active pharmaceutical ingredient often, especially is mixed with oral compositions.When being mixed with the other drug compositions, wish also that sometimes active pharmaceutical ingredient has lipotropy.Crystallization rasagiline alkali may be useful to it being mixed with the pharmaceutical composition of wishing low water solubility.For example, the compositions of percutaneous dosing can be prepared by lipophilic chemical compound.Such transdermal composition comprises ointment, Emulsion and patch.
The United States Patent (USP) 6,126,968 of investing people such as Peskin that can be used for that the object lesson of the medicinal acceptable carrier of formulate oral dosage forms and excipient on October 3rd, 1 announced.Be applicable to that technology and compositions that the present invention prepares dosage form see following reference material: 7 Modern Pharmaceutics, Chapter 9and 10 (Banker﹠amp; Rhodes, Editors, 1979); Pharmaceutical Dosage Forms:Tablets (Liebermanetal., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2
NdEdition (1976); Remington ' s Pharmaceutical Sciences, 17
ThEd. (MackPublishingCompany, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David 6anderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers:Therapeutic Applications:Drug and the Pharmaceutical Sciences, Vol61 (Alain Rolland, Ed., 1993); Drug Delivery to the gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences.Series in Pharmaceutical Technology; J.G.Hardy, S.S.Davis, Clive G.Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, and Vol 40 (Gilbert S.Banker, Christopher T.Rhodes, Eds.).
Tablet can comprise suitable bonding, lubricant, disintegrating agent, coloring agent, flavoring agent, flow-induction agent, and thawing agent.For example, tablet or capsule for oral unit dosage form, active pharmaceutical ingredient can with oral, avirulent, medicinal acceptable inert carrier, such as combinations such as lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, Sorbitol, microcrystalline Cellulose.The binding agent that is fit to comprises starch, gelatin, the natural sugar as glucose or beta lactose, corn starch, picture arabic gum, Calculus Bovis from Northwest of China cyanines glue (tragacanth), the perhaps such natural and rubber polymer of sodium alginate, polyvidone (pividone), carboxymethyl cellulose, Polyethylene Glycol, paraffin, etc.The lubricant that is used for these dosage forms comprises enuatrol, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, Talcum etc.Disintegrating agent includes but not limited to starch, methylcellulose, agar, bentonite (bentonite), xanthan gum (xanthan gum), cross-linking sodium carboxymethyl cellulose, sodium starch glycollate etc.
US6,126,968 full content is referenced and is incorporated into this, and the stability that it has disclosed the compositions that comprises PAI can be significantly improved by the relatively large certain alcohols of fusion.Especially, this alcohol is selected from penta hydroxy group alcohol or hexahydroxy alcohols (United States Patent (USP) 6,126,968).Typically, this alcohol is selected from mannitol, xylitol or Sorbitol (US6,126,968).Said composition can also further comprise citric acid (US6,126,968).
(R)-PAI itself can prepare according to the described method of embodiment 6B of for example WO95/11016.
Percutaneous dosage form and transdermal patch
The percutaneous dosage form is the patch that is stained with medicine that places skin, and it sees through skin release medicine in time and enters blood flow.Miscellaneous medicine can utilize transdermal patch to carry, for example, and the nicotine of smoking cessation usefulness, the scopolamine that is used for motion sickness, be used for climacteric and prevent the estrogen that sclerotin is loose, be used for anginal nitroglycerin, slow down the lignocaine of belt-shaped blister pain.Some drugs must with other material fusion, such as alcohol, to improve the ability of their transdermals.Yet insulin and many other molecules of medicine are too big, wear only skin.Endermic patch comprises the liner of one deck protection plaster when storing by several important forming, medicine, and binding agent, a skim (with of the release of control medicine) from Chu Chizhong, one deck substrate is not subjected to the influence of external environment condition with the protection plaster.The endermic plaster of two kinds of general types is matrix type and Chu Chixing.(" Transdermal Patches " Wikipedia.November15,2007, Wikipedia Foundation, Inc., December 13,2007
Http:// en.wikipedia.org/wiki/TransdermalPatch; And Reminmgton, The Science and Practice of Pharmacy, 20
ThEdition, 2000).
In the type patch of storage pond, medicine combines such as mineral oil with nonvolatile inert fluid, and the medicine in matrix type patch preparations is dispersed in the lipophilic or hydrophilic polymeric matrix, in the polymer such as acrylic acid or ethylene.Adhesive polymer such as polyisobutylene, is used to patch is fixed on the skin.(Stanley?Scheindlin，(2004)“Transdermal?Drug?Delivery：PAST，PRESENT，FUTURE，”MolecularInterventions，4：308-312)。
Major limitation through dermal delivery of drugs is the inherent barrier of skin.Often in endermic pharmaceutical dosage form, add penetration enhancer to disintegrate skin surface, accelerate the conveying of medicine.Typical penetration enhancer comprises high boiling alcohols, dihydroxylic alcohols, and fatty acid ester, the solvent of oleic acid and glycerol ester group, general concentration of adding is 1-20% (w/w).(Melinda?Hopp，“Developing?Custom?Adhesive?Systems?for?Transdermal?Drug?Delivery?Products，”Drug?Deliver)
In the percutaneous patch, also can be with rasagiline and other drug such as levodopa (Levodopa), L-carbidopa (L-carbidopa), beserazide, ladostigil, perhaps riluzole (riluzole) is blended together.
Experimental detail-first group: the crystalline preliminary preparation of rasagiline
Embodiment 1-utilizes and takes apart and extraction separation rasagiline alkali
Except taking apart the tartrate by adding NaOH, the preparation of rasagiline mesylate is according to United States Patent (USP) 5,532 basically, and the description of 415 embodiment 6B is carried out, and the rasagiline free alkali is separated as oil; Add methanesulfonic acid subsequently and form mesylate.
The rasagiline mesylate of 120 grams is dissolved in the deionized water of 700ml, adds the toluene of 400ml again, this mixture alkalizes to pH about 14 with 25% NaOH solution.After the stirring, be divided into biphase; Extract the water of lower floor with the toluene of 200ml.Phase-splitting, water discards.
Two methylbenzene extraction things are merged, steam solvent under the decompression.Obtain the yellow oily rasagiline alkali of 88.5 grams, its fusing point is lower than 20 ℃.
The liquid rasagiline alkali of getting 25.1 grams is as sample.This sample is mixed with ethanol, steam solvent under the decompression.The rasagiline alkali yellow oily residue of remaining 22.6 grams after ethanol evaporation is fallen.This oily rasagiline alkali keeps several weeks and unautogenous crystallization under oily.
Embodiment 2-utilizes and takes apart and extraction separation rasagiline alkali
155 grams are basically according to United States Patent (USP) 5,532, and rasagiline tartrate that the description of 415 embodiment 6B is prepared and 20 grams are dissolved in the water of 800ml according to the rasagiline mesylate of embodiment 1 preparation.The toluene that adds 400ml in this solution, this mixture alkalizes about 14 to pH with 25% NaOH solution, and is heated to 45 ± 5 ℃.
After the stirring, be divided into biphase.With the toluene of 200ml under 45 ± 5 ℃ with twice of the aqueous extraction of lower floor.Merge organic facies, water discards.
Organic facies with the merging of 200ml deionized water wash.Under reduced pressure steam solvent then, add the isopropyl alcohol of 50ml in the residue that obtains.Steam solvent under the decompression, add the isopropyl alcohol of 50ml again, steam solvent under the decompression subsequently.Formed the liquid rasagiline alkali of 100g syrup sample.
Embodiment 3-separates from water and spontaneous crystallization
The rasagiline mesylate of 15 grams under agitation is dissolved in the water of 150ml.This solution is cooled to 5 ℃, slowly adds 25% NaOH solution.When adding alkali, with batch temperature maintenance at 3-5 ℃.Reach at 7.5 o'clock at pH and observe solid sediment.PH reaches after 11, stops to add NaOH solution, stirs down and cools off feed liquid 1 hour, filters.Filter and carry out fast.Wash solid product on filter with water, decompression is dry down.
Obtain the rasagiline alkali solid of doing of 8.8 grams, yield 91.6%.Recording this solid fusing point is 38.2-38.4 ℃.
Embodiment 4-fusion-crystallization
6 grams are dissolved in the isopropyl alcohol of 20ml by the melicera rasagiline alkali of the acquisition of embodiment 1 after steaming toluene.This solution places hot bath to be evaporated to solvent by Rotary Evaporators under the 12mbar vacuum and is steamed fully.The isopropyl alcohol of reuse 20ml repeats this evaporation process with this residue dissolving.The residue that obtains places room temperature spontaneous crystallization after following a few hours.The solid crystal residue is confirmed as rasagiline alkali.Obtained the solid crystal alkali of 5.2 grams.Yield is quantitative.
Embodiment 5-adds the alcoholic solution of rasagiline in the water
2.4 gram is dissolved in the ethanol of 2.4 grams by the rasagiline alkali that embodiment 1 obtains.Under stirring this drips of solution is added in the cold water (0-5 ℃) of 5ml, in the dropping process, formed white precipitate.Cooling was stirred this mixture that obtains about 30 minutes down, filtered then.Filter fast, solid product is dried to constant weight under vacuum.
Obtain the solid crystal rasagiline of 2.15 grams, yield 89.6%.
Analyze: the chromatographic purity of HPLC～100%, HPLC content～99.0%.
Embodiment 6-adds entry in the alcoholic solution of rasagiline
3 grams are dissolved in the ethanol of 5ml by the rasagiline alkali that embodiment 1 obtains.Stir this solution under the room temperature, and add the water of 4.5ml.Do not precipitate.Cool off the solution that this obtains, observe the precipitation of whiteness in the time of 12 ℃.This mixture is cooled to about 0 ℃, under this temperature, stirred 30 minutes, filter then.Filter fast, on filter, wash this solid product with water, vacuum drying.
Obtain the solid crystal rasagiline of 2.72 grams, yield 90.0%.
Analyze: the chromatographic purity of HPLC～100%, HPLC content～100.0%.
Embodiment 7-adds the aqueous isopropanol of rasagiline in the water
8.2 gram is dissolved in the isopropyl alcohol of 10ml by the rasagiline alkali that embodiment 1 obtains.Stir this solution under the room temperature, and add the water of 14ml.Do not precipitate.Cool off the solution that this obtains, observe the precipitation of whiteness in the time of 17 ℃.Add the deionized water of 20ml in this mixture, this mixture further is cooled to about 0 ℃, under this temperature, stirred 30 minutes, filter then.
Filter fast.On filter, wash this solid product with water, vacuum drying.
Obtain the solid crystal rasagiline of 5.96 grams, yield 72.7%.
Analyze: the chromatographic purity of HPLC～100%, HPLC content～99.7%.
Embodiment 8-adds entry in the aqueous isopropanol of rasagiline
Batch A
The rasagiline alkali of 148 grams (48 grams restrain from embodiment 2 from embodiment 1,100) is dissolved in the isopropyl alcohol of 100.0ml.This solution is cooled to 17 ℃, under this temperature, adds the water of 252ml.This solution is cooled to 10 ℃, drops into solid rasagiline alkali crystal seed.Observing crystallization immediately takes place.The water that adds 100ml in this mixture.This mixture is cooled to 1 ℃, under this temperature, stirred 30 minutes, filter then.On filter, use this solid product of 200ml water washing, vacuum drying.
Obtain the solid crystal rasagiline of 138.9 grams, yield 93.8%.The fusing point that uncovered capillary tube method records is 39.0-39.2 ℃.
Analyze: the chromatographic purity of HPLC～100%, HPLC content～98.5%.
Batch B
Mother solution and the cleaning mixture of batch A are merged, have solid product from this mixture, to be precipitated out.Utilization filters to isolate yellow substance, and is dry under the vacuum.
Obtain the solid crystal rasagiline alkali of 1.5 grams, yield 1.0%.
Discuss
Discovery embodiment 3-8 synthetic solid crystal rasagiline alkali have high purity.
Crystallization rasagiline alkali to all batches all records same fusing point numerical value (utilizing differential scanning calorimetry (DSC) is 41 ℃, and the fusing point that uncovered capillary tube method records is 38-40 ℃).Find low-level volatile matter (moisture and residual solvent) by Ka Er Fischer aquametry (KF) and thermogravimetry (TGA).This shows that crystallization rasagiline alkali is nonhygroscopic.
Find that crystallization rasagiline alkali is dissolved in polarity and nonpolar solvent-alcohols, acetone, ethyl acetate, toluene, diethyl ether ， diox, hexane, and normal heptane fully.
By the analysis of powder x-ray diffraction (XRD) and DSC method, find that the solid rasagiline alkali of all batches is highly crystalline.All experiments that feature XRD and fourier infrared (FTIR) collection of illustrative plates and reproducible narrow fusion range and enthalpy show embodiment 3-8 batch have identical polymorphic and form.This crystal form is designated as crystalline form I.
The X-ray diffraction instrument that is adopted is a Scintag X-ray powder diffractometer, model X ' TRA, copper pipe, solid-state detector.
Specimen holder: circular standard aluminum specimen holder, band zero background quartz disk, resonant cavity diameter 25 (diameter) * 0.5 (deeply) mm.
Sweep parameter: scope: 2 θ 2-40 °;
Scan pattern: continuous sweep;
Stepping length: 0.05 °;
Speed: 5 °/minute.
In being listed in the table below according to the peak value of the sample of embodiment 4 preparation.The peak value of feature is listed with boldface letter.
The FTIR of sample is analyzed as follows:
Instrument: Perkin Elmer Spectrum One FT-IR Spectrometer S/N 58001
Parameter: sample adopts the DRIFT pattern to analyze.All collection of illustrative plates scannings 16 times.Resolution: 4.0cm-1.
Prepared all solids rasagiline alkali sample is rendered as white crystalline powder (remove the embodiment exception of batch B, it is separated as yellow powder) in this research.Microscopic examination shows that crystallization condition influences granularity and form consumingly.Seeded crystallization produces big, conventional non-accumulative crystallization, and spontaneous sedimentary result forms little aggregated particle.The difference of particle shape and polymorphic are irrelevant.
The form and the granularity of the crystallization rasagiline alkali of the foregoing description are listed in the table below.The mensuration of form and granularity is by microscopic examination.
| Embodiment | Form | Particle size range (μ m) |
| 4 | Irregular particle | 250-1000 |
| 5 | Little pole | 5-50 |
| 6 | Pole | 30-150 |
| 7 | Accumulative little pole | 5-50 |
| 8 | Pole | 250-2000 |
(1) Shi rasagiline half tartrate contains the residual solvent of about 10-15% and 0.7% S-isomer.
(2) raceme RAI alkali, oil, PAI content-94% is recorded by HPLC.
Embodiment 9-takes apart from isopropyl alcohol-water and precipitates, and drops into the emulsion crystallization of crystal seed
The rasagiline tartrate (1) of 70.0 grams is stirred low suspension in the deionized water of 320ml.This suspension is heated to 45 ℃, adds the 25%NaOH solution of 31ml and the toluene of 160ml.Stir this mixture, resulting emulsion leaves standstill.Biphase separating, the water of lower floor (pH=13-14) discards.The toluene on upper strata washs down in 45 ℃ with the deionized water of 100ml mutually, leaves standstill.The water of lower floor (pH=9-10) discards.
With evaporimeter reduction vaporization toluene solution, treat that solvent evaporation adds the isopropyl alcohol of 50ml after intact in the residue, continues to evaporate.
After evaporation is finished, add the isopropyl alcohol of 25ml, under similarity condition, isopropyl alcohol is steamed.
With residue, the oil of R-PAI alkali (33.9 gram) is dissolved in the isopropyl alcohol of 41ml.
This solution is cooled to 15 ℃, under cooling and stirring condition, adds the deionized water of 58ml in 2 hours in batches.In adding the water process, form buttery precipitation.The emulsion of resulting oil in water stirred 1 hour down at 1-3 ℃, do not observed crystallization.
Under 1-3 ℃, this batch dropped into crystallization rasagiline alkali crystal seed, the heat release crystallization has taken place immediately.In resulting slurry, add the water of 50ml to improve agitatability with mobile.This batch of restir 30 minutes filters then.Wash solid with water, vacuum drying under the room temperature.
The solid that obtains 31.5 grams is done R-PAI alkali, and yield 92% is based on oil.Figure 11 is the microgram of this rasagiline alkali.
Analyze :-40.8 ℃ of fusing points (DSC method), S-isomer (HPLC mensuration) 0.02%, purity (HPLC mensuration)-100%, content (HPLC mensuration)-98%.
Embodiment 10-takes apart from isopropyl alcohol-water and precipitates, the seeded crystallization from isopropyl alcohol-aqueous solution
The husky lucky rum stone hydrochlorates of 100.0 Crays (1) are stirred low suspension in the 458ml deionized water, add 229ml toluene and 46ml 25%NaOH solution.With this mixture heated to 45 ℃, stirred 15 minutes down at 45 ℃, under this temperature, leave standstill.
Biphase separately the water of lower floor (pH=13-14) discards, and uses the toluene phase on the deionized water wash upper strata of 140ml.Leave standstill resulting emulsion, biphase separating.The water of lower floor (pH=9-10) discards, with evaporimeter reduction vaporization toluene solution.
After treating that solvent evaporation is intact, add the isopropyl alcohol of 60ml in the residue, continue to evaporate.
After evaporation is finished, add the isopropyl alcohol of 50ml, under similarity condition, isopropyl alcohol is steamed.
With residue, the oil of R-PAI alkali (46.4 gram) is dissolved in the isopropyl alcohol of 56ml.
This solution is cooled to 16 ℃, under cooling and stirring condition, adds the deionized water of 147.5ml in 3 hours in batches.In adding the water process, observed precipitation and produced, in this batch, drop into crystallization R-PAI alkali crystal seed immediately.
Resulting suspension is cooled to 2 ℃, under this temperature, stirs and spend the night, filter it then.Wash solid with water, vacuum drying under the room temperature.
The solid that obtains 48.1 grams is done R-PAI alkali, and yield 96% is based on oil.Figure 12 is the microgram of this rasagiline alkali.
Analyze :-41.3 ℃ of fusing points (DSC method), S-isomer (HPLC mensuration) 0.01%, purity (HPLC mensuration)-100%, content (HPLC mensuration)-96%.
Embodiment 11-raceme PAI alkali crystallization (AF-8026) precipitates from isopropyl alcohol-water
The oil (2) of the 51.0 raceme PAI alkali that restrain is dissolved in the 50ml isopropyl alcohol.From this solution, steam solvent down with the evaporimeter decompression.
Residue (49.4 gram) is dissolved in the 60ml isopropyl alcohol, stirs and cooling.The deionized water that under cooling and stirring condition, in batches adds 156ml in 3 hours.In adding the water process, form the oily precipitation.In this batch, drop into crystallization rasagiline alkali crystal seed, do not see crystallization.
The aqueous emulsion of the oil that obtains was stirred 1 hour down at 3 ℃, do not see crystallization.
Stir in the process of spending the night this batch spontaneous crystallization down at 1 ℃.Filter this solid, but it begins fusing in filter process.Under the room temperature, this solid product in 1-2 minute on filter fully liquidization.
Before the fusing this material is being taken a sample fully.
Analyze: S-isomer (HPLC mensuration) 49.4%, content (HPLC mensuration)-87%.
Discuss
The above embodiments 9,10 and 11 show that at room temperature crystalline ability is a kind of intrinsic property of pure rasagiline alkali (R-isomer).Raceme PAI alkali at room temperature only exists with liquid state, and its fusing point is (embodiment 11) between 1 to 18 ℃.
The crystallization process that these embodiment have also shown the rasagiline alkali that contains the S-isomer impurities significantly purification crystallized product.The initial substance that contains 0.7% S-isomer is prepared to the solid crystal rasagiline of the S-isomer that only contains 0.01-0.02%.
Describe as previous embodiment, embodiment 9,10 and 11 has also shown the same trend of crystallized product granularity.Produce bigger granularity at 10-16 ℃ of slow crystallization process (embodiment 9) that drops into crystal seed down than the emulsion crystallization process under 1-3 ℃ (embodiment 10).
Conclusion
Above-mentioned experimental demonstration the various methods that prepare crystallization R (+)-N-propargyl-1-aminoidan.
First kind of method for preparing crystallization R (+)-N-propargyl-1-aminoidan comprises: a) with the salt formation solution soluble in water of a kind of R (+)-N-propargyl-1-aminoidan; B) described solution is cooled to about 0-15 ℃; C) the described solution of alkalization is to the about 11 formation suspensions of pH; And d) from this suspension, obtains described crystallization R (+)-N-propargyl-1-aminoidan.
The another kind of method for preparing crystallization R (+)-N-propargyl-1-aminoidan comprises: first organic solution that a) obtains liquid R (+)-N-propargyl-1-aminoidan; B) decompression steams solvent from this first organic solution down fully, forms residue; C) this residue is dissolved in second organic solvent, forms second organic solution; D) decompression steams this second organic solvent from this second organic solution down fully, forms residue; And e) this second residue is maintained 0-25 ℃, form crystallization R (+)-N-propargyl-1-aminoidan.
Also have the another kind of method for preparing crystallization R (+)-N-propargyl-1-aminoidan to comprise: a) to obtain crystallization R (+)-solution of N-propargyl-1-aminoidan in a kind of water miscible organic solvent; B) this solution and water are blended together; C) described solution is cooled to 0-20 ℃ and forms crystallization R (+)-N-propargyl-1-aminoidan; And d) separates this crystallization R (+)-N-propargyl-1-aminoidan.
The crystallization R (+) that obtains-N-propargyl-1-aminoidan can differentiate that its 2 θ peak values are 8.5,12.6,16.1 and 16.9 ° ± 0.2 ° by the powder x-ray diffraction collection of illustrative plates
Crystallization rasagiline alkali can differentiate by the powder x-ray diffraction collection of illustrative plates further that its 2 θ peak values are 20.3,20.9,25.4,26.4 and 28.3 ° ± 0.2 °
Crystallization rasagiline alkali can identify by fusing point further that the fusing point that adopts uncovered capillary tube method to record is 38-39 ℃, and the fusing point that perhaps adopts differential scanning calorimetry to record is 41 ℃.
But, adopt the resulting crystallization rasagiline of previous embodiment alkali not do.Therefore, carried out further drying.
Experimental detail-second group: the drying of rasagiline and raceme PAI alkali
Embodiment 12-24 provides the rate of sublimation of rasagiline alkali and raceme PAI alkali under different condition.
Embodiment 25-37 provide rasagiline alkali crystallization and dry after water content and the percentage yield of dry labor thing.
Crystallization experiment carries out in the glass reactor of the strap clamp cover of 100ml and 250ml, and this reactor has agitator, circulation oil bath and thermometer.In reactor, add the Dropping funnel that liquid adopts 25ml.Solid product adopts buchner funnel (Buchner filter) to filter, and places on the glass pallet of vacuum drying oven dry.
The distillation of embodiment 12-rasagiline alkali under the temperature of the pressure of 2-3mbar and 21 ℃
The internal diameter that the rasagiline alkali of about 4 grams is added to standard Sigma-Aldrich glass apophorometer (Cat.No.Z221171-1EA) is in the distillation pond of 3cm.These instrument and equipment have vacuum pump, and vacuometer and circulation ice-water bath are with the distillation medicated cap of cooling instrument.Shut instrument, 0-1 ℃ coolant begins to circulate.Being evacuated to pressure (" P ") is 2-3mbar, and the distillation pond is placed in temperature (" T ") and maintains in 21 ℃ the water bath with thermostatic control.
Process forms the solid that distils out by visualization and controls on the distillation medicated cap.After distillation finishes, note the time of operation, open instrument, take off the solid that distillation comes up, weigh from medicated cap.
Average rate of sublimation calculates by the following method:
Average rate of sublimation Rs1:
The Rs1=m/Mt[gram
-1Hour
-1]
Average rate of sublimation Rs2:
The Rs2=m/St[grammeter
-2Hour
-1]
Average rate of sublimation R relatively:
R=m100/Mt[%/hour]
The quality of m=sublimate, gram
The quality of M=initial substance, gram
T=distils the time, hour
S=sublimation area (sectional area of instrument), m2
After 8 hours, obtain the distillation rasagiline of 10mg, yield 0.25%.Average rate of sublimation Rs1=3.12x10
-5Ke Ke
-1Hour
-1The Rs2=1.333 grammeter
-2Hour
-1R=0.0312%/hour.
The distillation of embodiment 13-rasagiline alkali under the pressure of 2-3mbar and 35 ℃
Except T=35 ℃, other experimental procedures are with embodiment 1.
5.33 after hour, obtain the distillation rasagiline of 25mg, yield 0.62%.Average rate of sublimation Rs1=1.17x10
-3Ke Ke
-1Hour
-1The Rs2=4.978 grammeter
-2Hour
-1R=0.116%/hour.
The distillation of embodiment 14-rasagiline alkali under the pressure of 2-3mbar and 60 ℃
Except T=60 ℃, other experimental procedures are with embodiment 1.In the time of 60 ℃, initial rasagiline is liquid (fusion).
4.0 after hour, obtain the distillation rasagiline of 890mg, yield 22.4%.Average rate of sublimation Rs1=5.62x10
-2Ke Ke
-1Hour
-1The Rs2=236.19 grammeter
-2Hour
-1R=5.6%/hour.
The distillation of embodiment 15-rasagiline alkali under the pressure of 20mbar and 21 ℃
Except P=20mbar, other experimental procedures are with embodiment 1.
8.5 after hour, obtain the distillation rasagiline of 0mg, yield 0.0%.Average rate of sublimation Rs1=0.0 gram gram
-1Hour
-1The Rs2=0.0 grammeter
-2Hour
-1R=0.0%/hour.
The distillation of embodiment 16-rasagiline alkali under the pressure of 40mbar and 21 ℃
Except P=40mbar, other experimental procedures are with embodiment 1.
8.5 after hour, obtain the distillation rasagiline of 0mg, yield 0.0%.Average rate of sublimation Rs1=0.0 gram gram
-1Hour
-1The Rs2=0.0 grammeter
-2Hour
-1R=0.0%/hour.
The distillation of embodiment 17-rasagiline alkali under the pressure of 40mbar and 35 ℃
Except T=35 ℃ and P=40mbar, other experimental procedures are with embodiment 1.
5.33 after hour, obtain the distillation rasagiline of 8mg, yield 0.20%.Average rate of sublimation Rs1=3.75x10
-4Ke Ke
-1Hour
-1The Rs2=1.593 grammeter
-2Hour
-1R=0.0375%/hour.
The distillation of embodiment 18-rasagiline alkali under the pressure of 20mbar and 35 ℃
Except T=35 ℃ and P=20mbar, other experimental procedures are with embodiment 1.
5.33 after hour, obtain the sublimed rasagiline of 11mg, yield 0.27%.Average rate of sublimation Rs1=5.15x10
-4Ke Ke
-1Hour
-1The Rs2=2.192 grammeter
-2Hour
-1R=0.0506%/hour.
The distillation of embodiment 19-rasagiline alkali under the pressure of 40mbar and 60 ℃
Except T=60 ℃ and P=40mbar, other experimental procedures are with embodiment 1.In the time of 60 ℃, initial rasagiline is liquid (fusion).
5.33 after hour, obtain the distillation rasagiline of 25mg, yield 0.62%.Average rate of sublimation Rs1=1.17x10
-3Ke Ke
-1Hour
-1The Rs2=4.978 grammeter
-2Hour
-1R=0.116%/hour.
The distillation of embodiment 20-rasagiline alkali under the pressure of 20mbar and 60 ℃
Except T=60 ℃ and P=20mbar, other experimental procedures are with embodiment 1.In the time of 60 ℃, initial rasagiline is liquid (fusion).
5.33 after hour, obtain the distillation rasagiline of 162mg, yield 4.1%.Average rate of sublimation Rs1=7.64x10
-3Ke Ke
-1Hour
-1The Rs2=32.26 grammeter
-2Hour
-1R=0.769%/hour.
The distillation of embodiment 21-raceme PAI oil under the pressure of 20mbar and 22 ℃
Except initial substance is a raceme PAI oil, outside T=22 ℃ and the P=20mbar, other experimental procedures are with embodiment 1.
After 8 hours, obtain the distillation raceme PAI of 0mg, yield 0.0%.Average rate of sublimation Rs1=0.0 gram gram
-1Hour
-1The Rs2=0.0 grammeter
-2Hour
-1R=0.0%/hour.
The distillation of embodiment 22-raceme PAI oil under the pressure of 20mbar and 35 ℃
Except initial substance is a raceme PAI oil, outside T=35 ℃ and the P=20mbar, other experimental procedures are with embodiment 1.
5.33 after hour, obtain the distillation raceme PAI of 0mg, yield 0.0%.Average rate of sublimation Rs1=0.0 gram gram
-1Hour
-1The Rs2=0.0 grammeter
-2Hour
-1R=0.0%/hour.
The distillation of embodiment 23-raceme PAI oil under the pressure of 2-3mbar and 22 ℃
Except initial substance is a raceme PAI oil, outside T=22 ℃, other experimental procedures are with embodiment 1.
3.0 after hour, obtain the distillation raceme PAI of 10mg, yield 0.25%.Average rate of sublimation Rs1=8.33x10
-4Ke Ke
-1Hour
-1The Rs2=3.537 grammeter
-2Hour
-1R=0.08%/hour.
The distillation of embodiment 24-raceme PAI oil under the pressure of 2-3mbar and 60 ℃
Except initial substance is a raceme PAI oil, outside T=60 ℃, other experimental procedures are with embodiment 1.
1.3 after hour, obtain the distillation raceme PAI of 130mg, yield 3.25%.Average rate of sublimation Rs1=2.50x10
-2Ke Ke
-1Hour
-1The Rs2=101.16 grammeter
-2Hour
-1R=2.5%/hour.
Embodiment 25-adds water in the alcoholic solution of rasagiline alkali
The dried rasagiline tartrate of 23 grams and NaOH (20 grams, 25% solution) are in water-toluene mixture (75: reaction under the stirring 95ml).Mixture is left standstill, isolate water (pH＞11), organic facies washes with water, uses the Rotary Evaporators vaporising under vacuum.The dehydrated alcohol that adds 30ml then is so far in the residue, evaporation.
Repeat to add dehydrated alcohol and vacuum evaporating solvent.
The oil of residue-15.4 gram stirs down and is dissolved in the dehydrated alcohol of 19.5ml.
Stir this alcoholic solution, add 27ml water down, in this batch of material, drop into the crystal of solid rasagiline alkali then as crystal seed at 18-20 ℃.Observe crystallization immediately.This batch of material is cooled to 10-15 ℃, adds the water of 11ml again.
Subsequently, this batch of material is cooled to 0-5 ℃, under this temperature, stirred 30 minutes, filter.Water with 30ml washs this solid on filter.
Wet solid (16.0 gram) is at 25 ℃ and reduce pressure and (be dried to constant weight under the 4-5mbar.Adopt Karl Fischer (KF) method to measure the water content of dry labor thing.
The water content that the KF method records=0.18.
Dry labor thing=14.0 grams, yield=90.9%.
Embodiment 26-adds water in IPA (isopropyl alcohol) solution of rasagiline alkali
The dried rasagiline tartrate of 23 grams and NaOH (20 grams, 25% solution) are in water-toluene mixture (75: reaction under stirring 95ml).Mixture is left standstill, isolate water, organic facies washes with water, uses the Rotary Evaporators vaporising under vacuum.The isopropyl alcohol that adds 30ml then is so far in the residue, evaporation.
Repeat to add isopropyl alcohol and vacuum evaporating solvent.
The oil of residue-16.0 gram stirs down and is dissolved in the isopropyl alcohol of 19.5ml.
Stir this solution,, in this batch of material, drop into the crystal of solid rasagiline alkali then as crystal seed at 18-20 ℃ of water that adds 27ml down.Observe crystallization immediately.This batch of material is cooled to 10-15 ℃, adds the water of 11ml again.
Subsequently this batch of material is cooled to 0-5 ℃, under this temperature, stirred 30 minutes, filter.Water with 30ml washs this solid on filter.
Wet solid (16.9 gram) is dried to constant weight under 25 ℃ and reduce pressure (4-5mbar).Adopt the KF method to measure the water content of dry labor thing.
The water content that the KF method records=0.21%.
Dry labor thing=14.8 grams, yield=92.5%.
Embodiment 27-adds rasagiline alkali (oil) in IPA-water
The dried rasagiline tartrate of 23 grams and NaOH (20 grams, 25% solution) are in water-toluene mixture (75: reaction under stirring 95ml).Mixture is left standstill, isolate water, organic facies washes with water, uses the Rotary Evaporators vaporising under vacuum.The isopropyl alcohol that adds 30ml then is so far in the residue, evaporation.
Repeat to add isopropyl alcohol and vacuum evaporating solvent.
The oil of residue-16.0 gram is added to the solution (20: 27ml) of isopropyl alcohol-water under cooling and stirring.In the process of refueling with temperature maintenance more than 40 ℃ to prevent the spontaneous crystallization of free alkali.
With the temperature maintenance of isopropyl alcohol-aqueous solution in 0-5 ℃.After adding, under this temperature, stirred this mixture 30 minutes, filter.Water with 30ml washs this solid on filter.
Wet solid (16.8 gram) is dried to constant weight under 25 ℃ and reduce pressure (4-5mbar).Adopt the KF method to measure the water content of dry labor thing.
The water content that the KF method records=0.06%.
Dry labor thing=13.9 grams, yield=86.7%.
Embodiment 28-adds rasagiline alkali (oil) in cold water
The dried rasagiline tartrate of 23 grams and NaOH (20 grams, 25% solution) are in water-toluene mixture (75: reaction under stirring 95ml).Mixture is left standstill, isolate water, organic facies washes with water, uses the Rotary Evaporators vaporising under vacuum.The isopropyl alcohol that adds 30ml then is so far in the residue, evaporation.
Repeat to add isopropyl alcohol and vacuum evaporating solvent.
The oil of residue-16.0 gram is added in the cold water (0-5 ℃) in cooling with under stirring.In reinforced process, batch temperature is maintained below 5 ℃.Add the isopropyl alcohol flushing Dropping funnel of back, flushing liquor is added in the reactor goes with 6ml.Stirred resulting suspension 30 minutes down at 0-5 ℃, filter.
Discovery has a large amount of solid products to be deposited on agitator and the reactor surface, and homogeneity and the flowability of observing slurry are all very poor.
Water with 30ml washs this solid on filter.
Wet solid (15.3 gram) is dried to constant weight under 25 ℃ and reduce pressure (4-5mbar).Adopt the KF method to measure the water content of dry labor thing.
The water content that the KF method records=0.10%.
Dry labor thing=14.1 grams, yield=88.2%.
Embodiment 29-adds the alcoholic solution of rasagiline alkali in the water
The dried rasagiline tartrate of 23 grams and NaOH (20 grams, 25% solution) are in water-toluene mixture (75: reaction under stirring 95ml).Mixture is left standstill, isolate water, organic facies washes with water, uses the Rotary Evaporators vaporising under vacuum.The dehydrated alcohol that adds 30ml then is so far in the residue, evaporation.
Repeat to add ethanol and vacuum evaporating solvent.
The oil of residue-16.0 gram mixes with the dehydrated alcohol of 10ml, then cool off and stirring under be added to cold water (0 ℃, T
j=-4 ℃) in.In reinforced process, batch temperature is maintained 0 ℃.
Add the dehydrated alcohol flushing Dropping funnel of back, flushing liquor is added in the reactor goes with 5ml.Stirred resulting suspension 30 minutes down at 0 ℃, filter.
Discovery has a large amount of solid products to be deposited on agitator and the reactor wall, and homogeneity and the flowability of also observing slurry are all very poor.Water with 30ml washs this solid on filter.
Wet solid (16.0 gram) is dried to constant weight under 25 ℃ and reduce pressure (4-5mbar).Adopt the KF method to measure the dry labor thing water content at end.
The water content that the KF method records=0.06%.
Dry labor thing=14.1 grams, yield=88.2%.
Embodiment 30-adds water toward the alcoholic solution of the rasagiline alkali of fusion AI and PAI
The dried rasagiline tartrate of 23 grams and NaOH (20 grams, 25% solution) are in water-toluene mixture (75: reaction under stirring 95ml).Mixture is left standstill, isolate water, organic facies washes with water, uses the Rotary Evaporators vaporising under vacuum.The dehydrated alcohol that adds 30ml then is so far in the residue, evaporation.
Repeat to add ethanol and vacuum evaporating solvent.
The oil of residue-16.0 gram and the dehydrated alcohol of 40ml, 1 gram raceme PAI alkali (B.N.2499800407) and 0.5 gram aminoidan (Aminoindan) (B.N.2500300104) mix.
Solvent vacuum from the solution that obtains is steamed, from 17.5 the gram residues in the sampling 1.5 the gram (sample 1).
Then, residue (16.0 gram) is dissolved in the dehydrated alcohol of 20ml.In cooling with under stirring water (27ml) was added in this alcoholic solution with 10 minutes.In the reinforced process, batch temperature maintains 17-18 ℃.
After reinforced the finishing, drop into solid rasagiline alkali as crystal seed in this solution, crystallization produces.The water that adds 11ml again in the reactor.With the suspension cooling that obtains, stirred 30 minutes down at 1-2 ℃, filter.Water with 30ml washs this solid on filter.
Wet solid (16.1 gram) is dried to constant weight under room temperature and decompression (25mbar).
Dry labor thing=14.2 grams, yield=88.7%.
Embodiment 31-adds water in isopropyl alcohol (IPA) solution of rasagiline alkali
The dried rasagiline tartrate of 23 grams and NaOH (20 grams, 25% solution) are in water-toluene mixture (75: reaction under stirring 95ml).Mixture is left standstill, isolate water, organic facies washes with water, uses the Rotary Evaporators vaporising under vacuum.The isopropyl alcohol that adds 30ml then evaporates to residue.
Residue (15.9 gram) is dissolved in the isopropyl alcohol of 19.5ml.Spent be added in this solution in 10 minutes in water (27ml) in cooling with under stirring.In the reinforced process, batch temperature maintains 14-19 ℃.
After adding, drop in this solution solid rasagiline alkali as crystal seed, crystallization produces.The water that adds 11ml again in the reactor.With the suspension cooling that obtains, stirred 30 minutes down at 1-2 ℃, filter.Water with 30ml washs this solid on filter.
Wet solid (15.5 gram) is dried to constant weight under room temperature and decompression (25mbar).Adopt the KF method to measure the water content of dry labor thing.
The water content that the KF method records=0.20%.
Dry labor thing=14.9 grams, yield=93.7%.
Embodiment 32-adds water in the alcoholic solution of rasagiline alkali
The dried rasagiline tartrate of 23 grams and NaOH (20 grams, 25% solution) are in water-toluene mixture (75: reaction under stirring 95ml).Mixture is left standstill, isolate water, organic facies washes with water, uses the Rotary Evaporators vaporising under vacuum.The ethanol that adds 30ml then is so far in the residue, evaporation.
Residue (15.9 gram) is dissolved in the ethanol of 19.5ml.Spent be added in this solution in 10 minutes in water (27.2ml) in cooling with under stirring.In the reinforced process, batch temperature maintains 14-18.5 ℃.This batch of material is cooled to 12 ℃ of (T
j=10 ℃), in this solution, drop into solid rasagiline alkali as crystal seed.Produce crystallization immediately.The water that adds 11ml in the reactor.With the suspension cooling that obtains, stirred 30 minutes down at 1-2 ℃, filter.Water with 30ml washs this solid on filter.
Wet solid (17.0 gram) is dried to constant weight under room temperature and decompression (25mbar).Adopt the KF method to measure the water content of dry labor thing.
The water content that the KF method records=0.17%.
Dry labor thing=15.0 grams, yield=94.3%.
Embodiment 33-adds water toward the alcoholic solution of the rasagiline alkali of fusion AI and PAI
The dried rasagiline tartrate of 23 grams and NaOH (20 grams, 25% solution) are in water-toluene mixture (75: reaction under stirring 95ml).Mixture is left standstill, isolate water, organic facies washes with water, uses the Rotary Evaporators vaporising under vacuum.The dehydrated alcohol that adds 30ml then is so far in the residue, evaporation.
Repeat to add ethanol and vacuum evaporating solvent.
The oil of residue-16.0 gram and the dehydrated alcohol of 40ml, the aminoidan (B.N.2500300104) of the raceme PAI alkali (B.N.2499800407) of 0.5 gram and 0.25 gram mixes.
Solvent is steamed under the vacuum from the solution that obtains, from 16.75 the gram residues in the sampling 0.75 the gram (sample 1).
Then, residue (16.0 gram) is dissolved in the 20ml dehydrated alcohol.Spent be added in this alcoholic solution in 10 minutes in water (27ml) in cooling with under stirring.In the reinforced process, batch temperature maintains 17 ℃.
After reinforced the finishing, drop into solid rasagiline alkali as crystal seed in this solution, crystallization produces.The water that adds 11ml again in the reactor.With the suspension cooling that obtains, stirred 30 minutes down at 1-2 ℃, filter.Water with 30ml washs this solid on filter.
Wet solid (16.5 gram) is dried to constant weight under room temperature and decompression (25mbar).Adopt the KF method to measure the water content of dry labor thing.
The water content that the KF method records=0.21%.
Dry labor thing=14.9 grams, yield=93.1%.
Embodiment 34-adds water in the alcoholic solution of rasagiline alkali
The dried rasagiline tartrate of about 23 grams (20.13 gram) and NaOH (20 grams, 25% solution) are in water-toluene mixture (75: reaction under stirring 95ml).Mixture is left standstill, isolate water, organic facies washes with water, uses the Rotary Evaporators vaporising under vacuum.The ethanol that adds 30ml then evaporates to residue.
Residue (13.9 gram) is dissolved in the 19.5ml ethanol.Spent be added in this solution in 10 minutes in water (27.2ml) in cooling with under stirring.In the reinforced process, batch temperature maintains 17 ℃.In this batch of material, drop into solid rasagiline alkali, produce crystallization immediately as crystal seed.The water that adds 11ml again in the reactor.With the suspension cooling that obtains, stirred 30 minutes down at 1-2 ℃, filter.Water with 30ml washs this solid on filter.
Wet solid (15.4 gram) is dried to constant weight under room temperature and decompression (25mbar).(sample 2) adopts the KF method to measure the water content of dry labor thing.
The water content that the KF method records=0.14%.
Dry labor thing=13.1 grams, yield=94.2%.
Embodiment 35-adds water in the alcoholic solution of rasagiline alkali
The rasagiline tartrate of doing of 26 grams and NaOH (20 grams, 25% solution) are in water-toluene mixture (75: reaction under stirring 95ml).Mixture is left standstill, isolate water, organic facies washes with water, with vaporising under vacuum in the Rotary Evaporators.The ethanol that adds 30ml then is so far in the residue, evaporation.
Residue (17.9 gram) is dissolved in the ethanol of 19.5ml.Spent be added in this solution in 10 minutes in water (27.2ml) in cooling with under stirring.In the reinforced process, batch temperature maintains 19 ℃.This batch of material is cooled to 13 ℃, and drops into solid rasagiline alkali as crystal seed.Produce crystallization immediately.The water that adds 11ml again in the reactor.With the suspension cooling that obtains, stirred 30 minutes down at 1-2 ℃, filter.Having observed some solid products is deposited on the reactor wall.Water with 30ml washs this solid on filter.
Wet solid (19.9 gram) is dried to constant weight under room temperature and decompression (25mbar).Adopt the KF method to measure the dry labor thing water content at end.
The water content that the KF method records=0.18%.
Dry labor thing=17.1 grams, yield=95.5%.
Embodiment 36-adds water in the alcoholic solution of rasagiline alkali
The dried rasagiline tartrate of 23 grams and NaOH (20 grams, 25% solution) are in water-toluene mixture (75: reaction under stirring 95ml).Mixture is left standstill, isolate water, organic facies washes with water, uses the Rotary Evaporators vaporising under vacuum.The ethanol that adds 30ml then evaporates to residue.
Residue (15.9 gram) is dissolved in the 16ml ethanol.Spent be added in this solution in 10 minutes in water (27.2ml) in cooling with under stirring.In the reinforced process, batch temperature maintains 14-19 ℃.This batch of material is cooled to 13 ℃ of (T
j=10 ℃), and drop into solid rasagiline alkali as crystal seed.Produce crystallization immediately.The water that adds 11ml again in the reactor.With the suspension cooling that obtains, stirred 30 minutes down at 1-2 ℃, filter.Water with 30ml washs this solid on filter.
Wet solid (17.3 gram) is dried to constant weight under room temperature and decompression (25mbar).Adopt the KF method to measure the water content of dry labor thing.
The water content that the KF method records=0.18%.
Dry labor thing=15.2 grams, yield=95.6%.
Embodiment 37-adds water in the alcoholic solution of rasagiline alkali
The rasagiline tartrate of doing of 23 grams and NaOH (20 grams, 25% solution) are in water-toluene mixture (75: reaction under stirring 95ml).Mixture is left standstill, isolate water, organic facies washes with water, uses the Rotary Evaporators vaporising under vacuum.The ethanol that adds 30ml then is so far in the residue, evaporation.
Residue (16.0 gram) is dissolved in the ethanol of 19.5ml.Spent be added in this solution in 10 minutes in water (25ml) in cooling with under stirring.In the reinforced process, batch temperature maintains 17 ℃.This batch of material is cooled to 13 ℃ of (T
j=10 ℃), and drop into solid rasagiline alkali as crystal seed.Produce crystallization immediately.The water that adds 25ml again in the reactor.With the suspension cooling that obtains, stirred 30 minutes down at 1-2 ℃, filter.Water with 30ml washs this solid on filter.
Wet solid (19.3 gram) is dried to constant weight under room temperature and decompression (25mbar).Adopt the KF method to measure the water content of dry labor thing.
The water content that the KF method records=0.22%.
Dry labor thing=15.1 grams, yield=94.4%
The result sums up
The initial substance of embodiment 1-13 (solid rasagiline alkali, fusion rasagiline alkali, perhaps raceme PAI), sublimation condition, the yield after the distillation, and average rate of sublimation is listed in the following table 1.
The parameter of the crystallization of rasagiline alkali and dry run and condition among the embodiment 14-26, the moisture of dry labor thing, and the percentage yield of dry run is summarized in the table 2.
Discuss
Data show that rasagiline alkali and raceme PAI alkali have similar sublimability, and promptly the R-isomeric compound is similar to the rate of sublimation of racemic mixture.
Vacuum and temperature are figured in Fig. 1 and Fig. 2 for the influence of rasagiline alkali and raceme PAI alkali rate of sublimation.
The temperature (60 ℃ and higher) that these figure have proved under fine vacuum (pressure is lower than 3mbar) and raise is observed high rate of sublimation.
These figure have also proved under moderate vacuum (pressure is higher than 20mbar) and low temperature (being lower than 22 ℃), and observed rate of sublimation is zero.
These figure have also further proved temperature between 0 ℃ and 20 ℃, and pressure is between 4-25mbar the time, and exsiccant rasagiline contains the water of 0.06-0.22% weight, and the yield of dry labor thing is between 86.7%-95.6% weight.
Conclusion
After crystallization, the drying condition that solid rasagiline alkali is removed solvent can be recommended as moderate vacuum (pressure is higher than 20mbar) and low temperature (being lower than 35 ℃).
Three groups of experimental detail-Di: the drying of rasagiline alkali and purification
Prepare the rasagiline alkali that contains 27.8% isopropyl alcohol with wet rasagiline tartrate.
1. production method
Described the multiple method for preparing rasagiline alkali among the PCT International Publication No. WO2008/076348, its content is incorporated into this by reference.Prepared a collection of according to described method.
1.1 method
Embodiment 38. preparation rasagiline alkali solids-extensive
Production process comprises following operation:
A. take wet rasagiline tartrate apart with NaOH:
B. the rasagiline alkali that will dissociate is separated with the oily product;
C. rasagiline alkali is dissolved in the ethanol, by the crystallization of the inductive rasagiline alkali of the crystal seed that adds water;
D. filter and wash solid product; And
E. drying solid rasagiline alkali.
Because rasagiline alkali is low melting point, so it just is processed to medicine without grinding.
Procedure parameter and condition are summarized in following table 1.1-1.3.
Procedure parameter-the tartrate of table 1.1 rasagiline alkali preparation is taken apart and rasagiline alkali separating step
The preparation process parameter of table 1.2 rasagiline alkali-rasagiline alkali crystallisation step
*-account for the percentage ratio of whole adding water yields
Procedure parameter-the filtration of table 1.3 separating solids rasagiline alkali, washing, drying
1.2. result and discussion
When batch producing, the drying that the spontaneous crystallization of oil of two technical barrier relevant with large-scale production-rasagiline alkali and solid product arranged to no effect.
Except above-mentioned 2, the S-content of isomer in the medicine reaches 0.35%, far above the level (NMT.0.1%) of specification.
Below go through with regard to these 3.
1.2.1. the crystallization and the dissolving of rasagiline alkali oil
At the oil of the rasagiline alkali of separating between operating procedure 1.2 and 1.3 under nitrogen protection and cooling, store overnight in reactor.This alkali solidifies, and forms one at reactor bottom.Be dissolved in the dehydrated alcohol in more than two hours as hyaloid rasagiline sodium carbonate.
The proposal scheme that addresses this problem is between operation 2 and 3, prevents rasagiline alkali oil resinification by keeping its alcoholic solution.Carried out the laboratory simulation experiment to estimate the influence of this method variation to yield and crystallized product purity.
1.2.1.1. laboratory scale simulation
Two batches of rasagiline alkali have been prepared to simulate the storage situation of the alcoholic solution of rasagiline alkali under the different temperatures.
Experiment and result see for details following:
(7-8 ℃) kept 48 hours in alcoholic solution under the oil cooling of embodiment 39. rasagiline alkali
17.0 the oil of gram rasagiline alkali is dissolved in the 17 gram dehydrated alcohol.Gained solution is placed refrigerator, kept 48 hours down at 7-8 ℃.To this alcoholic solution sampling (sample 1).
This settled solution is added in the glass reactor of strap clamp cover of 100ml, this reactor configurations has agitator, thermometer and circulation oil bath.
With reactor cooled (T
j=11 ℃), stir the 8 gram water of adding down.Then, drop into solid rasagiline alkali, observe crystallization as crystal seed.This batch of material was stirred 15 minutes down at 11-12 ℃, add 33.8 gram water again.The suspension of gained is cooled to 4 ℃, stirred 30 minutes down at 1-4 ℃.Solid is filtered, with twice of 17ml water washing.Wet solid product (17.6 gram) is dry under vacuum.
Dry labor thing-15.7 gram
Crystallization yield-92%
Analyze:
Sample 1 (solution):
The purity that HPLC records:
S-isomer-0.77%
IDD-1-aminoidan-L.T.0.05% (QL)
The dry labor thing:
Color-Bai is to off-white
Content-99.5%
IDD-N.D. (do not detect)
S-isomer-0.01%
m.p.-39.5-40.4℃
The water content that the KF method records-0.2% weight.
Grease chamber's relaxing the bowels with purgatives of warm nature of embodiment 40. rasagiline alkali kept in alcoholic solution 48 hours
17.0 the oil of the rasagiline alkali of gram is dissolved in the 17 gram dehydrated alcohol.Gained solution was kept 48 hours down in room temperature (20-28 ℃).To this alcoholic solution sampling (sample 1).
This settled solution is added in the glass reactor of strap clamp cover of 100ml, this reactor configurations has agitator, thermometer and circulation oil bath.
With reactor cooled (T
j=11 ℃), stir the 8 gram water of adding down.Then, drop into solid rasagiline alkali, observe crystallization as crystal seed.This batch of material was stirred 20 minutes down at 11-12 ℃, add 33.8 gram water again.The suspension of gained is cooled to 4 ℃, stirred 30 minutes down at 1-4 ℃.Batch of material is filtered, twice of the water washing of usefulness 17ml.Wet solid product (18.2 gram) is dry under vacuum.
Dry labor thing-15.9 gram
Crystallization yield-93.5%
Analyze:
Sample 1 (solution):
Color-Huang
The purity that HPLC records:
S-isomer-0.76%
IDD-1-aminoidan-L.T.0.05% (QL)
The dry labor thing:
Content-99.9%
IDD-does not detect
S-isomer-0.01%
Fusion range-39.6-40.6 ℃
The water content that the KF method records-0.1% weight.
1.2.1.2. the result discusses and conclusion
Above-mentioned data showed that before crystallization the alcoholic solution of rasagiline alkali is placed on yield and the quality that did not influence solid product in the air in 48 hours.By the crystallization rasagiline moral purity of the formulations prepared from solutions that is stored in low temperature (7-8 ℃) with identical by the purity of the crystallization rasagiline that stores formulations prepared from solutions at room temperature.
Therefore, the rasagiline alkali between separation and crystallization process should be stored in the alcoholic solution.This operator scheme has prevented the spontaneous crystallization of rasagiline alkali oil and the problem of being brought by its dissolving.
1.2.2. it is dry
Wet rasagiline alkali does not have to stir under vacuum (23-30mmHg) and room temperature (23 ℃) condition came to nothing in dry 14 hours.Solid still wets, water content 28%.
After 14 hours static drying, stir (8rpm) this filter cake, the exsiccator chuck progressively was heated to 35 ℃ through 9 hours.Significantly accelerate in this step dry rate-the filter cake sampling, find that the solid water content only is 15%.
Under similarity condition, continue this dry run 17 hours (spending the night).Filter cake sampling then, discovery is to have done (moisture 0.07%).
Dry again 8 hours to water content do not make significant difference-water content of next sample is 0.05%.
Find above-mentioned drying condition (P＜35mmHg; T
j=35 ℃, mixing speed 8rpm) be effective to rasagiline alkali.
1.2.3. solid uniformity
In above-mentioned dry run, (Drug Substance is to make it uniform by prolonging in the dry run to stir DS) to medicine.Formulate in process of production and implemented a kind of special sample program to confirm the homogeneity and the uniformity of DS after drying.
From the zones of different of exsiccator the rasagiline alkali of doing is taken a sample 5 times.Each material of these 5 samples is mixed with into the 6th sample.To these 6 sample analysis water content, content, purity, fusing point, S-content of isomer and particle size distribution.Analysis result is shown in table 2.1; Tables of data is understood the uniformity of desciccate.
Table 2.1 rasagiline alkali sample analysis result
Digital proof in the last table this exsiccator provide effective homogenization for the rasagiline alkali of 3.5 kg batch.
1.2.4. the S-isomer in the solid product
Digital proof in the table 2.1 find that in the rasagiline alkali of this batch high-caliber S-isomer (OOS) is arranged.
These data astonish, because the levels typical of S-isomer is lower than 0.1% in the crystalline alkali.The content of this impurity of the rasagiline alkali of preparation is 0.02-0.03% on a small scale.S-content of isomer in crystallized product may be owing to contain this impurity more than 2% in the initial substance that uses in 0.35% level.
1.2.4.1. the simulation of crystallization process
The difference of process time is illustrated by the temperature curve that Fig. 3 contrasts pilot scale and laboratory batch.
Small-scale crystallization process spends about 2.5 hours usually, but then carries out 6.5 hours on a large scale.Below experimentation the influence of process time for optical purity.
The preparation of embodiment 41. rasagiline alkali
The wet rasagiline tartrate of 100 grams under agitation mixes with the water of 160ml.In this mixture, add the NaOH solution of 63 grams 25% and the toluene of 200 grams, stirred this batch of material 1 hour down, under this temperature, leave standstill half an hour then at 40-45 ℃ (pH=13).The aqueous phase separation of lower floor is come out to discard, add the water of 100ml in this batch of material.Subsequently, stir down this mixture half an hour, leave standstill half an hour at 40-45 ℃.The aqueous phase separation of lower floor is come out to discard.Evaporate with Rotary Evaporators under the organic facies vacuum on upper strata.Identical-total evaporation time of the temperature curve of evaporation process and pilot scale batch is 3 hours 20 minutes, and residue is through reaching 55 ℃ temperature in 1 hour 20 minutes, through reaching 60 ℃ temperature in 2 hours.
Steam after the toluene, in residue, add 75 dehydrated alcohol that restrain, continue evaporation process.All evaporation times are 2 hours 40 minutes, and the temperature of residue reaches 55 ℃ and then reach 60 ℃ in evaporation process.
With residual product-rasagiline alkali oil (52 gram) cooling, 5 ℃ of following store overnight.Then this alkali under agitation is dissolved in the dehydrated alcohol of 52 grams, adds the water of 24ml.Subsequently, the settled solution that obtains is cooled to 12.5 ℃, drops into crystallization rasagiline alkali as crystal seed.This crystallization batch was stirred 2 hours down at 11-12 ℃.Under cooling,, then, this batch was cooled to 4 ℃ through 1 hour 45 minutes, stirred 30 minutes down at 1-4 ℃ through dripping the water of 103 grams in 1 hour.
Half of this batch taken out from crystallizer, filter.Solid is with the water washing of 50ml, and is dry under the vacuum.To dry labor thing (26.2 gram) and filtrate (mother solution, mother liquor) sampling-sample 4 (solid) and 2 (M.L. mother solution).
With batch second half stir down in cooling (1 ℃) and spend the night, the full duration under T＜4 ℃ is 14 hours.Then this half batch of material is filtered, with the water washing solid of 50ml, dry under the vacuum.To dry labor thing (17.8 gram) and filtrate (mother solution) sampling-sample 7 (solids) and 5 (M.L. mother solutions).
Analyze:
Solid:
Sample 4:
S-isomer-N.D.
HPLC content-99.4%
HPLC measures purity (IDD)-N.D.
Fusion range-39.5-40.7 ℃
Sample 7:
S-isomer-N.D.
HPLC content-99.5%
HPLC measures purity (IDD)-N.D.
Fusion range-39.5-40.7 ℃
Mother solution:
Sample 2:
S-isomer-31.3%
HPLC records rasagiline concentration-5.8mg/ml
HPLC measures purity (IDD)-1-aminoidan (1-Aminoindan)-1.37%; RRT=1.47-0.03%; RRT=1.60-0.05%; 1-indone (1-Indanone)-0.15%, RRT=7.8-0.07%
Sample 5:
S-isomer-26.9%
HPLC records rasagiline concentration-6.8mg/ml
HPLC measures purity (IDD)-1-aminoidan-1.17%; RRT=1.47-0.03%; RRT=1.60-0.04%; 1-indone-0.13%
1.2.4.2. the result discusses and conclusion
It is not detectable adopting the level of the S-isomer in the rasagiline alkali that prolongs crystallization process (14 hours, sample 7) preparation.Find that this impurity has same level in 1 hour product of crystallization (sample 4).
In the table 3.1, the mother solution of small scale experiments is formed and large-scale mother solution compares.Table 3.1 demonstrates the closely similar of mother solution purity data in the simulation experiment and extensive batch.Simultaneously, approximately low 3 times of the S-isomer concentration ratio small scale experiments in the large-scale mother solution.
Table 3.1; The mother solution of rasagiline alkali crystallization process when laboratory and pilot scale formed
Racemization does not take place in data show R-isomer of rasagiline alkali under mass production conditions.The result of simulation experiment shows the optical purity did not influence of processing time for rasagiline alkali.
Problem for the S-isomer has two possible solutions:
I) to the recrystallization of the rasagiline alkali that polluted the S-isomer; And
Ii) initial substance-rasagiline tartrate being made further optics purifies.
Studied with this two kinds of ways small-scales and large-scale production rasagiline alkali medicine.Part is described this research below.
2. the optics of rasagiline alkali is purified
2.1. the recrystallization of rasagiline alkali-on a small scale
The rasagiline alkali that contains 0.35% S-isomer from the pilot scale of rejecting batches 255500208 carries out recrystallization at laboratory, and that adopts in the crystallisation step that is adopted and the pilot-scale is identical.
Embodiment 42. rasagiline alkali recrystallization
The dehydrated alcohol of the rasagiline alkali of 49.5 grams and 52 grams are added in the glass reactor that 0.5 liter strap clamp overlaps.Stir and heating (T
j=35 ℃) this batch of material dissolves fully until solid.
With this solution cooling, stir the water that adds 24 grams down.12 ℃ of solid rasagiline alkali that drop in the settled solution that obtains down as crystal seed are 11-12 ℃ of stirring 1 hour down.Observe crystallization in this step.
Cooling and stir and to spend the water that added 103 grams in 20 minutes down should batch be cooled to 4 ℃ then, and 2-4 ℃ of stirring 45 minutes down.
With this batch cooling,, be dried to constant weight under the vacuum with 2x50ml water washing solid.
To solid product (45.5 gram) sampling (sample 1).Filtrate (merging mother solution and cleaning mixture) is used the Rotary Evaporators vaporising under vacuum.To buttery evaporated residue (1.1 gram) sampling (sample 2), analyze with solid product.
Analyze:
Solid:
Sample 1:
S-isomer-N.D.
HPLC content-98.8%
HPLC measures purity (IDD)-3PAIO-L.T.0.05% (QL); 1-aminoidan-L.T.0.05% (QL); 1-indone (1-Indanone)-L.T.0.05% (QL)
Fusion range-39.1-39.8 ℃
Mother solution:
Sample 2 (residue after the evaporation):
HPLC content-91.3%
S-isomer-7.8%
HPLC measures purity (IDD)-3PAIO-L.T.0.05% (QL); 1-aminoidan-L.T.0.2%; RRT=0.92-0.08%; RRT=1.62-0.13%; RRT=2.27-0.05%; 1-indone-L.T.0.05% (QL); RRT=6.6-0.1%; Whole IDD-0.5%
2.2. discuss and conclusion
The probability that having experimental results show that of more than describing in detail come out the S-isomer separation from the rasagiline alkali that contains this impurity of 0.35%S-isomer fully.The discovery of the optics purification process under this result and the former laboratory scale is consistent.
3. the purification of rasagiline tartrate
3.1 general consideration
The lucky rum stone of the thunderous sand of crystallization rasagiline salt hydrochlorate might cause the S-isomer to be separated fully from its tartrate.The rasagiline tartrate that contains the purification of very low-level S-isomer can be converted to the almost nil rasagiline alkali of this impurity content, and the optical purity of extensive batch of this impurity effect.
The probability that the recrystallization of having studied the rasagiline tartrate is purified with the further optics of estimating this intermediate.
3.2. the recrystallization of rasagiline tartrate
3.2.1 step evaluates
Carried out the crystallization experiment of rasagiline tartrate in the glass reactor of 0.5 liter strap clamp cover, this reactor is equipped with agitator, for circulation oil bath, condenser and the thermometer of heating and cooling.Come drying solid with vacuum drying oven.
All experiments all adopt the S-content of isomer as 0.7% initial substance.Utilize HPLC to analyze the IDD and the S-isomer of solid and product liquid.
The crystallization process of embodiment 43. from the water of 8 times of volumes
In reactor, add the rasagiline tartrate of 50.0 grams and the water of 300ml, stir this mixture and heating (T
j=85 ℃), in the time of 72 ℃, observe solid and dissolved fully.
Reactor is slowly cooled off, drop into the rasagiline tartrate in the time of 63 ℃ as crystal seed.Observe crystallization subsequently, through 2 hours with reactor cooled to 20 ℃.Stir 30 minutes after-filtration of this batch of material down at 20 ℃, with the water washing solid of 30ml, 50 ℃ of following vacuum dryings are to constant weight.
Wet solid-36.9 gram
Dried solid-26.7 gram
Yield-70.9%
Analyze:
Solid:
Outward appearance-white solid
S-isomer-0.01% area
1-aminoidan＜0.08% adopts HPLC check analysis standard substance to record
IDD-does not see other peak
Mother solution:
S-isomer-2.48% area
1-aminoidan-0.26% area, the IDD-RRT=1.96-0.01% area; The RRT=2.29-0.02% area, the main peak area of contrast rasagiline
The slurry of embodiment 44. from the water of 4 times of volumes is to the recrystallization of slurry
In reactor, add the rasagiline tartrate of 50.0 grams and the water of 150ml, stir this mixture and heating (T
j=85 ℃) to 75 ℃, observe not dissolving of solid.
75 ℃ were stirred this slurry that obtains 90 minutes down, were cooled to 12 ℃ through 40 minutes.Stir 40 minutes these batch of materials of after-filtration down at 10-12 ℃, with the water washing solid of 40ml, 50 ℃ of following vacuum dryings are to constant weight.
Wet solid-38.4 gram
Dried solid-26.7 gram
Yield-71.1%
Analyze:
Solid:
Outward appearance-white solid
S-isomer-0.11% area
1-aminoidan＜0.08% adopts HPLC check analysis standard substance to record
IDD-does not see other peak
Mother solution:
S-isomer-2.62% area
1-aminoidan-0.35% area, the main peak area of IDD-RRT=1.96-0.02% area-contrast rasagiline
The slurry of embodiment 45. from the water of 4 times of volumes is to the slurry recrystallization, and the anti-solvent (anti-solvent) that batch B utilizes precipitates
Batch A:
In reactor, add the rasagiline tartrate of 50.0 grams and the preheating water (T of 150ml
j=85 ℃), stir this mixture and be heated to 75 ℃, observe solid and do not have dissolving.75-77 ℃ was stirred this slurry that obtains 90 minutes down, was cooled to 7 ℃ through 1 hour.Stir 40 minutes these batch of materials of after-filtration down at 5-7 ℃, with the water washing solid of 75ml, 50 ℃ of following vacuum dryings are to constant weight.
Wet solid-40.5 gram
Dried solid-30.7 gram
Yield-81.9%
Analyze:
Solid:
Outward appearance-white solid
S-isomer-0.11% area
1-aminoidan＜0.08% adopts HPLC check analysis standard substance to record
IDD-does not see other peak
Mother solution:
S-isomer-4.47%
1-aminoidan-0.62% area, the main peak area of IDD-RRT=1.96-0.06% area-contrast rasagiline
Batch B:
Filtrated stock from batch A is divided into two five equilibriums (every part of 70ml)
First part, precipitate with isopropyl alcohol
Mother solution is cooled to 7 ℃ under stirring, and adds the isopropyl alcohol (IPA) of 20ml, observes solid precipitation.Stir 30 minutes after-filtration of this suspension down at 5-7 ℃.Use the washed with isopropyl alcohol solid, 50 ℃ of following vacuum dryings are to constant weight.
Wet solid-0.9 gram
Dried solid-0.7 gram
Yield-1.9%
Analyze:
Solid:
Outward appearance-white solid
S-isomer-0.15% area
1-aminoidan＜0.08% adopts HPLC check analysis standard substance to record
IDD-does not see other peak
Mother solution:
S-isomer-8.36%
1-aminoidan-1.14% area, the IDD-RRT=0.37-0.02% area; The RRT=0.79-0.01% area; The RRT=1.32-0.01% area; The RRT=1.40-0.02% area; The RRT=1.88-0.03% area; The RRT=1.96-0.11% area; The main peak area of-contrast rasagiline
Second part, utilize ethanol to precipitate
Mother solution is cooled to 7 ℃ under stirring, and adds the ethanol of 20ml, observes solid precipitation.Stir 30 minutes after-filtration of this suspension down at 5-7 ℃.Use the washing with alcohol solid, 50 ℃ of following vacuum dryings are to constant weight.
Wet solid-0.9 gram
Dried solid-0.6 gram
Yield-1.6%
Analyze:
Solid:
Outward appearance-white solid
S-isomer-0.07% area
1-aminoidan＜0.08% adopts HPLC check analysis standard substance to record
IDD-does not see other peak
Mother solution:
S-isomer-6.76%
1-aminoidan-0.93% area, the IDD-RRT=0.37-0.01% area; The RRT=0.79-0.02% area; The RRT=1.32-0.01% area; The main peak area of RRT=1.96-0.08% area-contrast rasagiline
The recrystallization of embodiment 46. from the water of 4 times of volumes and the slurry the isopropyl alcohol to slurry
In reactor, add the rasagiline tartrate of 50.0 grams and the water of 150ml.Stir this mixture and heating (T
j=85 ℃) to 75 ℃, observe solid and do not have dissolving.77-79 ℃ was stirred this slurry that obtains 90 minutes down, is cooled to 25 ℃ then.The IPA that adds 40ml batch is cooled to 5 ℃.Stir 30 minutes these batches of after-filtration down at 5 ℃, with the IPA washing solid of 30ml, 50 ℃ of following vacuum dryings are to constant weight.
Wet solid-47.9 gram
Dried solid-35.9 gram
Yield-95.7%
Analyze:
Solid:
Outward appearance-white solid
S-isomer-0.07% area
1-aminoidan＜0.08% adopts HPLC check analysis standard substance to record
IDD-does not see other peak
The recrystallization of table 4.1 tartrate
Above result in the table 4.1 show that the rasagiline tartrate very provides high yield and high-optical-purity with slurry to the recrystallization of the mode of slurry effectively from the water of 4 times of volumes.Also carried out other work optimizing this method, and the evaluation procedure parameter is for the influence of rasagiline tartrate purification.
3.2.2. procedure parameterization
The following examples have been studied most important procedure parameter to the yield of recrystallization rasagiline tartrate and the influence of purity.
The recrystallization of embodiment 47. from the water of 4 times of volumes and the slurry the isopropyl alcohol to slurry, T
j=100 ℃
In reactor, add the rasagiline tartrate of 50.0 grams and the water of 150ml.Stir this mixture and heating (T
j=100 ℃) to 90 ℃, observed most solid and dissolved.90 ℃ were stirred this slurry that obtains 90 minutes down, are cooled to 25 ℃ then.The isopropyl alcohol that adds 40ml batch is cooled to 5 ℃.Stir 30 minutes after-filtration of this batch down at 5 ℃, with the washed with isopropyl alcohol solid of 30ml, 50 ℃ of following vacuum dryings are to constant weight.
Wet solid-57.7 gram
Dried solid-37.9 gram
Yield-93.7% (calculating) according to initial substance L.O.D.=20%
Analyze:
Solid:
Outward appearance-white solid
S-isomer-0.01% area
IDD-does not see other peak
1-aminoidan-N.D.
The recrystallization of embodiment 48. from the water of 4 times of volumes and the slurry the isopropyl alcohol to slurry, T
j=65 ℃
In reactor, add the rasagiline tartrate of 50.0 grams and the water of 150ml.Stir this mixture and heating (T
j=65 ℃) to 63 ℃, observe solid and do not have dissolving.63-64 ℃ was stirred this slurry that obtains 90 minutes down, is cooled to 25 ℃ then.The isopropyl alcohol that adds 40ml batch is cooled to 5 ℃.Stir 30 minutes these batches of after-filtration down at 5 ℃, with the washed with isopropyl alcohol solid of 30ml, 50 ℃ of following vacuum dryings are to constant weight.
Wet solid-55.0 gram
Dried solid-37.7 gram
Yield-94.5%
Analyze:
Solid:
Outward appearance-white solid
S-isomer-0.32% area
1-aminoidan＜0.08% adopts HPLC check analysis standard substance to record
IDD-does not see other peak
The recrystallization of embodiment 49. from the water of 4 times of volumes and the slurry the isopropyl alcohol to slurry, T
j=85 ℃, mixing time-15 minute
In reactor, add the rasagiline tartrate of 50.0 grams and the water of 150ml.Stir this mixture and heating (T
j=85 ℃) to 75 ℃, observed most solid and dissolved.75 ℃ were stirred this slurry that obtains 15 minutes down, are cooled to 25 ℃ then.The isopropyl alcohol that adds 40ml batch is cooled to 5 ℃.Stir 30 minutes these batches of after-filtration down at 5 ℃, with the washed with isopropyl alcohol solid of 30ml, 50 ℃ of following vacuum dryings are to constant weight.
Wet solid-55.0 gram
Dried solid-37.5 gram
Yield-93.7% (calculating) according to initial substance L.O.D.=20%
Analyze:
Solid:
Outward appearance-white solid
S-isomer-0.19% area
IDD-does not see other peak
1-aminoidan-N.D.
The recrystallization of embodiment 50. from the water of 4 times of volumes and the slurry the isopropyl alcohol to slurry, T
j=85 ℃, mixing time-150 minute
In reactor, add the rasagiline tartrate of 50.0 grams and the water of 150ml.Stir this mixture and heating (T
j=85 ℃) to 75 ℃, observed most solid and dissolved.75 ℃ were stirred this slurry that obtains 150 minutes down, are cooled to 25 ℃ then.The IPA that adds 40ml batch is cooled to 5 ℃.Stir 30 minutes these batches of after-filtration down at 5 ℃, with the IPA washing solid of 30ml, 50 ℃ of following vacuum dryings are to constant weight.
Wet solid-51.9 gram
Dried solid-38.4 gram
Yield-96.0% (calculating) according to initial substance L.O.D.=20%
Analyze:
Solid:
Outward appearance-white solid
S-isomer-0.10% area
IDD-does not see other peak
1-aminoidan-N.D.
The recrystallization of embodiment 51. from the water of 4 times of volumes and the slurry the isopropyl alcohol to slurry, T
j=85 ℃, the isopropyl alcohol of 100ml
In reactor, add the rasagiline tartrate of 50.0 grams and the water of 150ml.Stir this mixture and heating (Tj=85 ℃) to 75 ℃, observed most solid and dissolved.75 ℃ were stirred this slurry that obtains 90 minutes down, are cooled to 25 ℃ then.The isopropyl alcohol that adds 100ml batch is cooled to 5 ℃.Stir 30 minutes these batches of after-filtration down at 5 ℃, with the washed with isopropyl alcohol solid of 30ml, 50 ℃ of following vacuum dryings are to constant weight.
Wet solid-50.2 gram
Dried solid-37.7 gram
Yield-93.2% (calculating) according to initial substance L.O.D.=20%
Analyze:
Solid:
Outward appearance-white solid
S-isomer-0.10% area
IDD-does not see other peak
1-aminoidan-N.D.
The recrystallization of embodiment 52. from the water of 4 times of volumes and the slurry the isopropyl alcohol to slurry, T
j=85 ℃, prolong cool time
Add the rasagiline tartrate of 50.0 grams and the water of 150ml in the reactor.Stir this mixture and heating (T
j=85 ℃) to 75 ℃, observed most solid and dissolved.75 ℃ were stirred this slurry that obtains 90 minutes down, are cooled to 25 ℃ then.The isopropyl alcohol that adds 40ml batch is cooled to 2 ℃.Stir 12 hours these batches of after-filtration down at 1-2 ℃, with the washed with isopropyl alcohol solid of 30ml, 50 ℃ of following vacuum dryings are to constant weight.
Wet solid-52.5 gram
Dried solid-38.1 gram
Yield-95.2% (calculating) according to initial substance L.O.D.=20%
Analyze:
Solid:
Outward appearance-white solid
S-isomer-0.05% area
IDD-does not see other peak
1-aminoidan-N.D.
Following table 5 has been summed up the parametrization result of experiment.Data show that the recrystallization process parameter as processing time and temperature has very strong power of influence for the optical purity of tartrate.
Table 5.1 procedure parameter is for the influence of the purification of rasagiline tartrate
Recrystallization temperature is reduced to 63 ℃ from 75 ℃, and the recrystallization time was reduced to 15 minutes from 90 minutes causes the level of S-isomer the solid product significantly to increase.Simultaneously, observing procedure parameter does not make significant difference for yield.
Fig. 4 demonstrates in the recrystallization process of tartrate, and significant variation has taken place solid forms.The rasagiline tartrate that crystallizes out from isopropyl alcohol or any other organic solvent has the needle-like crystal habit.
As shown in Figure 4 and Figure 5, the acicular crystal of initial rasagiline tartrate changes into the rhabdolith of recrystallized product.
3.3. large scale purification rasagiline tartrate
According to the 3.2nd the joint described in program with extensive prepared in batches the rasagiline tartrate of two batches of purification.This process is based on embodiment 46.
This production is the result be summarized in the following table 6.1 and table 7.1.
The procedure parameter of the rasagiline tartrate that table 6.1 large-scale production is pure
The quality of the pure rasagiline tartrate that table 7.1 is extensive batch
4. the extensive reworking of rasagiline alkali
Embodiment 38 prepared that batch rasagiline alkali are come up to specification by reworking with the contents level (from 0.35%) that reduces the S-isomer.
The method of reworking is based on the recrystallization of embodiment 42.Obtained the product quality that high yield is become reconciled.Table 8.1 has compared the procedure parameter of laboratory scale and pilot scale reworking batch.The product quality of laboratory scale and pilot scale batch sees Table 9.1.
Tables of data open-birth product scale does not make significant difference for the result of reworking.QA/QC this batch of having let pass, it is used to stability test and prescription exploitation.
Table 8.1 on a small scale and the recrystallization parameter of extensive batch rasagiline alkali
The main mass parameter of table 9.1 small-scale and large-scale recrystallization rasagiline alkali
5. produce rasagiline alkali from the rasagiline tartrate of purification
Utilize the rasagiline tartrate of purification to produce two extensive batch rasagiline alkali.In addition, rasagiline alkali was maintained in the alcoholic solution before crystallization in process of production.
Below table 10.1,10.2 and 10.3 have summed up procedure parameter and condition with order progressively.The tables of data that presents among the table 10.1-10.3 is understood the process repeatability of large-scale production fashion and the scalable property of production stage.
The large-scale production tartrate of table 10.1 procedure parameter or rasagiline alkali is taken apart and the separating step of rasagiline alkali
The crystallisation step of the large-scale production rasagiline alkali of table 10.2 procedure parameter or rasagiline alkali
*This batch cooling system when preservation is spent the night breaks down
Separation-the filtration of the large-scale production solid rasagiline alkali of table 10.3 procedure parameter or rasagiline alkali, washing, drying steps
Prepared rasagiline alkali batch qualitative data be summarized in following table 11.1 and 11.2.
Tables of data is understood the high-purity of rasagiline alkali, and the repeatability of the physical property on pilot-scale.
The quality of table 11.1 rasagiline alkali DS
The physical property of table 11.2 rasagiline alkali DS
6. intermediate product-time restriction
Three new intermediate solid products are arranged in the step of producing rasagiline alkali medicine (DS):
-wet pure rasagiline tartrate
-dried pure rasagiline tartrate
-wet rasagiline alkali
Intermediate product can stop the long time in operating process.Carried out particular study to prove the stability of these materials under condition of storage.
6.1. small scale experiments
The stability test of the pure rasagiline tartrate that embodiment 53. wets
It contains isopropyl alcohol and water is stored in the poly sack wet pure rasagiline tartrate under room temperature (RT).To the solid sampling, be dried to constant weight, analyze.When sampling and analysing is zero in the time, after zero two weeks of counting and all around, carry out.The results are shown in following table 12.
The stability test of the pure rasagiline tartrate that embodiment 54. does
At embodiment? in the pure rasagiline tartrate of doing that makes under room temperature (RT), be stored in the poly sack.To the solid sampling and analysing, when the time is zero, after zero two weeks of counting and all around, carry out.The results are shown in following table 12.1.
The stability test of the rasagiline alkali that embodiment 55. wets
At embodiment? in the wet rasagiline alkali that makes its contain water and under room temperature (RT), be stored in the poly sack, there is aluminum lamination lucifuge the inside of sack.To the solid sampling, be dried to constant weight under the vacuum, analyze.When sampling and analysing is zero in the time, after zero two weeks of counting and all around, carry out subsequently.The results are shown in following table 13.1.
The stability test of the pure rasagiline tartrate that table 12.1. is wet and dried
*-wet rasagiline tartrate sample is dried before analysis
The stability test of the rasagiline alkali that table 13. is wet
6.2. result and discussion
The purity of all solids intermediate product did not change after the data of table 12.1 and table 13 showed around having stored.Products all behind the stability test around having finished is all up to specification.The time dimension of intermediate product is listed in the table 14.1 in the production process.
Table 14.1 rasagiline alkali intermediate product-time dimension
No product storage temperature, ℃ time dimension
The 1 pure rasagiline tartrate room temperature that wets one month
The 2 pure rasagiline tartrate room temperatures of doing one month
The 3 rasagiline alkali+2-+8 that wet one month
Claims (22)
1. water content is lower than crystallization R (+)-N-propargyl-1-aminoidan of 0.5% weight.
2. crystallization R as claimed in claim 1 (+)-N-propargyl-1-aminoidan, its water content is not higher than 0.06% weight.
3. pharmaceutical composition, said composition comprises R (+)-N-propargyl-1-aminoidan and medicinal acceptable carrier that water content is lower than 0.5% weight.
4. pharmaceutical composition as claimed in claim 3, said composition is used for oral by preparation.
5. pharmaceutical composition as claimed in claim 3, said composition are used for percutaneous by preparation and use.
6. pharmaceutical composition as claimed in claim 5 is a transdermal patch.
7. the method for a drying solid R (+)-N-propargyl-1-aminoidan, this method comprises makes solid R (+)--propargyl-1-aminoidan be exposed to temperature below 40 ℃ and pressure between 2-1013.3mbar suitably long time with drying solid R (+)-N-propargyl-1-aminoidan.
8. method for preparing the pharmaceutical composition that comprises the R (+) that water content is 0.5% weight-N-propargyl-1-aminoidan and medicinal acceptable carrier, this method comprises:
A) under the temperature below 40 ℃ and pressure between 2-1013.3mbar to the dry suitably long time of solid R (+)-N-propargyl-1-aminoidan with drying solid R (+)-N-propargyl-1-aminoidan; And
B) will combine by exsiccant R (+)-N-propargyl-1-aminoidan and the medicinal acceptable carrier that step a) obtains, thus pharmaceutical compositions.
9. as claim 7 or 8 described methods, it is characterized in that its baking temperature is below 35 ℃.
10. as any described method of claim 7-9, it is characterized in that its baking temperature is below 25 ℃.
11. any described method as claim 7-10 is characterized in that its drying pressure is higher than 20mbar.
12. any described method as claim 7-11 is characterized in that, is at least its drying time 45 hours.
13. a production comprises the method for crystallization R (+)-N-propargyl-1-aminoidan and at least a medicinal medicine checking of accepting carrier batch, this method comprises:
A) produce a collection of this medicine;
B) measure the moisture weight content of the sample of this batch; And
C) only when the water content of crystallization R (+)-N-propargyl-1-aminoidan of this batch is lower than 0.5% weight, verify the distribution of this batch.
14. method as claimed in claim 13 is characterized in that, only when the water content of crystallization R (+)-N-propargyl-1-aminoidan of this batch is lower than 0.06% weight, verifies this batch.
15. the method for a production crystallization R (+)-N-propargyl-1-aminoidan, this method comprises:
A) salt of purification R (+)-N-propargyl-1-aminoidan;
B) with R (+)-N-propargyl-1-aminoidan salt formation solution soluble in water of this purification;
C) described solution is cooled to 0-15 ℃;
D) described solution being alkalized to pH is that 9.5-12.5 forms a suspension; And
E) described crystallization rasagiline R (+)-N-propargyl-1-aminoidan is separated from this suspension.
16. method as claimed in claim 15 is characterized in that, step a) comprises:
I) with this R (+)-N-propargyl-1-aminoidan salt formation solution soluble in water;
Ii) in this solution, add a kind of water-soluble organic solvent;
Iii) this solution is cooled to about 0-10 ℃; And
Iv) from this suspension, obtain R (+)-N-propargyl-1-aminoidan salt of purification.
17. method as claimed in claim 16 is characterized in that, with respect to R (+)-N-propargyl-1-aminoidan before the crystallization, the optical purity of R (+)-N-propargyl-1-aminoidan salt of this purification that is v) obtained from step I increases.
18. any described method as claim 15-17 is characterized in that this R (+)-N-propargyl-1-aminoidan salt is tartrate.
19. the method for a production crystallization R (+)-N-propargyl-1-aminoidan, this method comprises:
A) obtain R (+)-solution of N-propargyl-1-aminoidan in a kind of water-soluble organic solvent;
B) and together with this solution and hydration;
C) described solution is cooled between 0-20 ℃, forms crystallization R (+)-N-propargyl-1-aminoidan;
D) fractional crystallization R (+)-N-propargyl-1-aminoidan; And
E) if the amount of S (+)-N-propargyl-1-aminoidan greater than 0.1% weight of the R (+) that in step d), is obtained-N-propargyl-1-aminoidan total amount, then repeating step is a)-d).
20. method as claimed in claim 19 is characterized in that, this water-soluble organic solvent is a kind of alcohol.
21. method as claimed in claim 20 is characterized in that, this described alcohol or ethanol, or isopropyl alcohol, or the mixture of ethanol and isopropyl alcohol.
22. any described method as claim 19-21 is characterized in that, with respect to R (+)-N-propargyl-1-aminoidan before the crystallization, the optical purity of this crystallization R (+)-N-propargyl-1-aminoidan increases.
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| US13248708P | 2008-06-19 | 2008-06-19 | |
| US61/132,487 | 2008-06-19 | ||
| PCT/US2009/003670 WO2009154777A2 (en) | 2008-06-19 | 2009-06-19 | Process for preparing and drying solid rasagiline base |
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| Publication Number | Publication Date |
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| CN102065853A true CN102065853A (en) | 2011-05-18 |
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| CN2009801235603A Pending CN102065853A (en) | 2008-06-19 | 2009-06-19 | Process for preparing and drying solid rasagiline base |
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| US (2) | US7968749B2 (en) |
| EP (1) | EP2299992A4 (en) |
| JP (1) | JP2011524907A (en) |
| CN (1) | CN102065853A (en) |
| AU (1) | AU2009260728B2 (en) |
| BR (1) | BRPI0909997A2 (en) |
| CA (1) | CA2727017A1 (en) |
| EA (1) | EA021472B1 (en) |
| IL (1) | IL209134A0 (en) |
| MX (1) | MX2010013875A (en) |
| NZ (1) | NZ589547A (en) |
| WO (1) | WO2009154777A2 (en) |
| ZA (1) | ZA201008755B (en) |
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| CN104619681A (en) * | 2012-08-31 | 2015-05-13 | 住友化学株式会社 | Method for producing (r)-1,1,3-trimethyl-4-aminoindane |
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2009
- 2009-06-19 JP JP2011514620A patent/JP2011524907A/en active Pending
- 2009-06-19 CA CA2727017A patent/CA2727017A1/en not_active Abandoned
- 2009-06-19 WO PCT/US2009/003670 patent/WO2009154777A2/en active Application Filing
- 2009-06-19 AU AU2009260728A patent/AU2009260728B2/en not_active Ceased
- 2009-06-19 NZ NZ589547A patent/NZ589547A/en unknown
- 2009-06-19 EP EP09767090.5A patent/EP2299992A4/en not_active Withdrawn
- 2009-06-19 MX MX2010013875A patent/MX2010013875A/en not_active Application Discontinuation
- 2009-06-19 BR BRPI0909997A patent/BRPI0909997A2/en not_active IP Right Cessation
- 2009-06-19 EA EA201170053A patent/EA021472B1/en not_active IP Right Cessation
- 2009-06-19 CN CN2009801235603A patent/CN102065853A/en active Pending
- 2009-06-19 US US12/456,643 patent/US7968749B2/en not_active Expired - Fee Related
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104619681A (en) * | 2012-08-31 | 2015-05-13 | 住友化学株式会社 | Method for producing (r)-1,1,3-trimethyl-4-aminoindane |
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0909997A2 (en) | 2015-10-27 |
| WO2009154777A2 (en) | 2009-12-23 |
| EP2299992A2 (en) | 2011-03-30 |
| MX2010013875A (en) | 2011-01-20 |
| US20090318564A1 (en) | 2009-12-24 |
| AU2009260728B2 (en) | 2015-01-29 |
| US7968749B2 (en) | 2011-06-28 |
| WO2009154777A4 (en) | 2010-07-01 |
| WO2009154777A9 (en) | 2011-01-27 |
| CA2727017A1 (en) | 2009-12-23 |
| JP2011524907A (en) | 2011-09-08 |
| ZA201008755B (en) | 2012-02-29 |
| EP2299992A4 (en) | 2015-10-21 |
| US8163960B2 (en) | 2012-04-24 |
| IL209134A0 (en) | 2011-01-31 |
| NZ589547A (en) | 2013-03-28 |
| EA021472B1 (en) | 2015-06-30 |
| US20110281953A1 (en) | 2011-11-17 |
| WO2009154777A3 (en) | 2010-05-06 |
| EA201170053A1 (en) | 2011-08-30 |
| AU2009260728A1 (en) | 2009-12-23 |
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